U.S. patent application number 15/577061 was filed with the patent office on 2018-06-28 for implant for treatment of an ocular condition.
The applicant listed for this patent is Allergan, Inc., ENVISIA THERAPEUTICS, INC.. Invention is credited to Andres Garcia, Tomas Navratil, Rhett Schiffman, Rozemarijn Suzanne Verhoeven.
Application Number | 20180177718 15/577061 |
Document ID | / |
Family ID | 57441717 |
Filed Date | 2018-06-28 |
United States Patent
Application |
20180177718 |
Kind Code |
A1 |
Garcia; Andres ; et
al. |
June 28, 2018 |
IMPLANT FOR TREATMENT OF AN OCULAR CONDITION
Abstract
The present disclosure relates to the field of pharmaceutical
compositions, ocular implants, and systems and methods for treating
an ocular condition. In certain aspects, the disclosure provides
ocular implant systems for treating post-operative inflammation. In
certain aspects, the ocular implants taught herein are rapid
release extended treatment implants.
Inventors: |
Garcia; Andres; (Durham,
NC) ; Verhoeven; Rozemarijn Suzanne; (Pittsboro,
NC) ; Navratil; Tomas; (Carrboro, NC) ;
Schiffman; Rhett; (Morrisville, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ENVISIA THERAPEUTICS, INC.
Allergan, Inc. |
Morrisville
Irvine |
NC
CA |
US
US |
|
|
Family ID: |
57441717 |
Appl. No.: |
15/577061 |
Filed: |
May 27, 2016 |
PCT Filed: |
May 27, 2016 |
PCT NO: |
PCT/US2016/034820 |
371 Date: |
November 27, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62168292 |
May 29, 2015 |
|
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62206535 |
Aug 18, 2015 |
|
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62260964 |
Nov 30, 2015 |
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62329769 |
Apr 29, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/10 20130101;
A61L 27/18 20130101; A61L 27/18 20130101; A61L 27/54 20130101; A61P
27/02 20180101; A61L 2430/16 20130101; A61K 9/0051 20130101; A61K
31/573 20130101; C08L 71/02 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 47/10 20060101 A61K047/10; A61P 27/02 20060101
A61P027/02; A61K 31/573 20060101 A61K031/573 |
Claims
1. An extended treatment rapid delivery system for treating
post-operative ocular inflammation in an eye of a patient in need
thereof, comprising: A) a biocompatible polymer matrix based ocular
implant rapid delivery vehicle; and B) at least one therapeutic
agent homogeneously dispersed within the polymer matrix, wherein
said ocular implant rapid delivery vehicle is formulated to
substantially disintegrate within 24 hours of being placed into the
eye, and wherein said disintegration of the ocular implant rapid
delivery vehicle results in substantially all of the at least one
therapeutic agent being released into the eye within 24 hours, and
wherein the at least one therapeutic agent provides a therapeutic
effect to the eye of the patient for at least 2 days, and wherein
said ocular implant rapid delivery vehicle is formulated to reduce
post-operative corneal thickening in a patient in need thereof.
2. The extended treatment rapid delivery system of claim 1, wherein
the at least one therapeutic agent provides a therapeutic effect to
the eye of the patient for at least 3 days.
3. The extended treatment rapid delivery system of claim 1, wherein
the at least one therapeutic agent provides a therapeutic effect to
the eye of the patient for at least 5 days.
4. The extended treatment rapid delivery system of claim 1, wherein
the at least one therapeutic agent provides a therapeutic effect to
the eye of the patient for at least 7 days.
5. The extended treatment rapid delivery system of claim 1, wherein
the at least one therapeutic agent provides a therapeutic effect to
the eye of the patient for at least 14 days.
6. The extended treatment rapid delivery system of claim 1, wherein
the at least one therapeutic agent provides a therapeutic effect to
the eye of the patient for at least 28 days.
7. The extended treatment rapid delivery system of claim 1, wherein
the at least one therapeutic agent has a low solubility under
normal human eye physiological conditions.
8. The extended treatment rapid delivery system of claim 1, wherein
the at least one therapeutic agent has a water solubility of about
0.0097 mg/mL.
9. The extended treatment rapid delivery system of claim 1, wherein
the biocompatible polymer matrix comprises poly(ethylene
glycol).
10. The extended treatment rapid delivery system of claim 1,
wherein the biocompatible polymer matrix comprises a mixture of two
or more poly(ethylene glycol) polymers of different molecular
weight.
11. The extended treatment rapid delivery system of claim 1,
wherein the biocompatible polymer matrix comprises a mixture of two
or more poly(ethylene glycol) polymers of different molecular
weight, wherein one of said polymers has a molecular weight of
about 3,350 and one of said polymers has a molecular weight of
about 100,000.
12. The extended treatment rapid delivery system of claim 1,
wherein the biocompatible polymer matrix comprises a mixture of two
or more poly(ethylene glycol) polymers of different molecular
weight, wherein one of said polymers has a molecular weight of
about 3,350 and is present in an amount of about 10-20 weight
percent of the total polymer and one of said polymers has a
molecular weight of about 100,000 and is present in an amount of
about 80-90 weight percent of the total polymer.
13. The extended treatment rapid delivery system of claim 1,
wherein the biocompatible polymer matrix comprises a mixture of two
or more poly(ethylene glycol) polymers of different molecular
weight, wherein one of said polymers has a molecular weight of
about 3,350 and is present in an amount of about 11 weight percent
of the total polymer and one of said polymers has a molecular
weight of about 100,000 and is present in an amount of about 89
weight percent of the total polymer.
14. The extended rapid delivery system of claim 1, wherein the
biocompatible polymer matrix comprises a mixture of two or more
poly(ethylene glycol) polymers of different molecular weight,
wherein one of said polymers has a molecular weight of about 3,350
and is present in an amount of about 7-10 weight percent of the
ocular implant and one of said polymers has a molecular weight of
about 100,000 and is present in an amount of about 57-76 weight
percent of the ocular implant, and wherein the at least one
therapeutic agent is present in an amount of about 15-35 weight
percent of the ocular implant.
15. The extended treatment rapid delivery system of claim 1,
wherein the biocompatible polymer matrix comprises a mixture of two
or more poly(ethylene glycol) polymers of different molecular
weight, wherein one of said polymers has a molecular weight of
about 3,350 and is present in an amount of about 4-7 weight percent
of the ocular implant and one of said polymers has a molecular
weight of about 100,000 and is present in an amount of about 35-54
weight percent of the ocular implant, and wherein the at least one
therapeutic agent is present in an amount of about 40-60 weight
percent of the ocular implant.
16-76. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present Application claims priority to U.S. Provisional
Application No. 62/168,292, filed on May 29, 2015, and U.S.
Provisional Application No. 62/206,535, filed on Aug. 18, 2015, and
U.S. Provisional Application No. 62/260,964, filed on Nov. 30,
2015, and U.S. Provisional Application No. 62/329,769, filed on
Apr. 29, 2016, the entire contents of each of which are hereby
incorporated by reference in their entirety.
FIELD
[0002] The present disclosure relates to the field of
pharmaceutical compositions, implants formed from pharmaceutical
compositions, systems of treating an ocular condition, methods of
forming implants, and methods of treating ocular conditions.
BACKGROUND
[0003] Cataracts affect more than 20 million Americans over the age
of 40 and cataract surgery is the most common ophthalmic surgery
performed in developed countries, with more than 3 million
surgeries performed in the United States every year. The most
common post-operative complication is anterior segment
inflammation. Corticosteroids are commonly used to suppress ocular
inflammation and their use following cataract surgery has become a
standard practice.
[0004] The topical corticosteroids currently available for
post-operative inflammation and pain suffer from several drawbacks.
First, the corticosteroids are dependent on ocular tissue
distribution for efficacy. This is problematic, because following
topical application of eye drops, generally 80% of the product is
eliminated via the nasolacrimal drainage, thus limiting delivery to
the target ocular tissues. Second, because up to 80% of the steroid
is eliminated via the nasolacrimal drainage, patients undergoing
regular treatment with these steroids suffer from prolonged
systemic exposure to the drug. And third, the present
corticosteroid treatments on the market suffer from significant
compliance problems. This may be due in part to the majority of
patients who are candidates for cataract surgery being of advanced
age, which is often associated with compliance problems,
particularly for topical steroids that require multiple times per
day dosing (Burns 1992, Chennamaneni 2013, Shell 1984, Winfield
1990).
[0005] Consequently, there is a need in the art for the development
of effective pharmaceutical compositions, delivery systems, and
methods for treating post-operative ocular pain and inflammation,
which do not suffer from these drawbacks.
BRIEF SUMMARY
[0006] The present disclosure addresses a crucial need in the art,
by providing an extended treatment and rapid delivery vehicle
pharmaceutical formulation that may be directly administered to the
subconjunctival region of an eye, or intracainerally placed, and
that does not suffer from the drawbacks of the current topical
application paradigm.
[0007] In certain embodiments, the disclosure relates to precisely
engineered biocompatible drug delivery systems and methods of
making and utilizing such systems. In aspects, the drug delivery
systems comprise a rapid release delivery vehicle that undergoes
complete or nearly complete dissolution upon exposure to the
physiological conditions of an eye, said dissolution of the
delivery vehicle leading to the complete release of therapeutic
agent cargo to the site of treatment.
[0008] The biocompatible drug delivery systems taught herein are,
in some embodiments, engineered using the PRINT.RTM. particle
technology (Envisia Therapeutics Inc., North Carolina). The
PRINT.RTM. technology allows for uniform size, shape, and dose
concentration in the disclosed drug delivery systems.
[0009] Further, the disclosure provides methods of utilizing the
taught precisely engineered biocompatible drug delivery systems to
treat, inter cilia, conditions of the eye and tissues surrounding
or associated with the eye.
[0010] Conditions preventable or treatable according to the present
disclosure include post-operative inflammation and/or pain that may
be due to a number of surgical procedures or injury.
[0011] In certain embodiments, the present disclosure relates to
pharmaceutical compositions for treating an ocular condition,
comprising: a biocompatible polymer matrix and at least one
therapeutic agent.
[0012] In certain embodiments, the present disclosure provides for
pharmaceutical compositions for treating an ocular condition,
comprising: an ocular implant. In aspects, the ocular implant
comprises a biocompatible polymer matrix that contains a
homogenously dispersed therapeutic agent therein. In some
embodiments, the ocular implant is a "non-extruded" ocular
implant.
[0013] In a particular embodiment, the disclosure provides a
pharmaceutical composition for treating an ocular condition, or
condition of the surrounding or associated tissues, comprising: A)
a biocompatible polymer matrix; and B) at least one therapeutic
agent homogenously dispersed within the polymer matrix.
[0014] In certain embodiments, the disclosure provides for an
extended treatment rapid delivery system for treating
post-operative ocular inflammation in an eye of a patient in need
thereof, comprising: A) a biocompatible polymer matrix based ocular
implant rapid delivery vehicle; and B) at least one therapeutic
agent homogeneously dispersed within the polymer matrix, wherein
said ocular implant rapid delivery vehicle is formulated to
substantially disintegrate within 24 hours of being placed into the
eye, and wherein said disintegration of the ocular implant rapid
delivery vehicle results in substantially all of the at least one
therapeutic agent being released into the eye within 24 hours, and
wherein the at least one therapeutic agent provides a therapeutic
effect to the eye of the patient for at least 2 days, and wherein
said ocular implant rapid delivery vehicle is formulated to reduce
post-operative corneal thickening in a patient in need thereof In
sonic aspects, the therapeutic agent has low solubility in water,
or is hardly soluble in water, or is not soluble in water. In some
aspects, the therapeutic agent is a corticosteroid. In some
aspects, the therapeutic agent is difluprednate. In some aspects
the biocompatible polymer matrix comprises polyethylene glycol)
(i.e. "PEG") polymers.
[0015] In certain embodiments, the biocotnpatible polymer matrix
comprises as a % w/w of the overall implant pharmaceutical
composition: about 5% to about 95% w/w, or about bout 5% to about
90% w/w, or about 5% to about 80%, or about 5% to about 70%, or
about 5% to about 60%, or about 10% to about 90% w/w, or about 10%
to about 80%, or about 10% to about 70%, or about 10% to about 60%,
or about 20% to about 90%, or about 20% to about 80%, or about 20%
to about 70%, or about 20% to about 60%, or about 30% to about 90%,
or about 30% to about 80%, or about 30% to about 70%, or about 30%
to about 60%, or about 40% to about 90%, or about 40% to about 80%,
or about 40% to about 70%, or about 40% to about 60% , or about 50%
to about 90%, or about 50% to about 80%, or about 50% to about 70%,
or about 50% to about 60%, or about 60% to about 90%, or about 60%
to about 85%, or about 65% to about 85%, or about 60% to about 80%,
or about 60% to about 70%; or about 45% to about 80%, or about 45%
to about 75%, or about 45% to about 70%, or about 45% to about 65%,
or about 45% to about 60%, or about 45% to about 55%, or about 45%
to about 50%, or about 70% to about 80%, or about 65% to about 85%,
or about 85% to about 95%, or about 92.5% to about 95%, or about
55% to about 70% w/w of the pharmaceutical composition.
[0016] In certain embodiments, the biocompatible polymer matrix is
comprised of a first polymer. In aspects, the first polymer
comprises as a % w/w of the biocompatible polymer matrix: about 1%
to about 100%, or about 1% to about 90% vv/w, or about 1% to about
80%, or about 1% to about 70%, or about 1% to about 60%, or about
1% to about 50%, or about 1% to about 40%, or about 1% to about
30%, or about 1% to about 20%, or about 1% to about 15%, or about
1% to about 10%, or about 1% to about 5%. In aspects, the first
polymer is a PEG polymer. In aspects, the PEG polymer is PEG 3,350.
In aspects, the PEG polymer (e.g., PEG 3,350) can be present as the
sole polymer in the biocompatible polymer matrix. In aspects, the
PEG polymer (e.g., PEG 3,350) can be present in a mixture of
polymers in the biocompatible polymer matrix.
[0017] In certain embodiments, the biocompatible polymer matrix is
comprised of a first polymer. In aspects, the first polymer
comprises as weight of the biocompatible polymer matrix: about 1
.mu.g to about 1,000 .mu.g, about 1 .mu.g to about 500 .mu.g, or
about 1 .mu.g to about 400 .mu.g, or about 1 .mu.g to about 300
.mu.g, or about 1 .mu.g to about 200 .mu.g, or about 1 .mu.g to
about 100 .mu.g, or about 1 .mu.g to about 50 .mu.g, or about 1
.mu.g to about 40 .mu.g, or about 1 .mu.g to about 30 .mu.g, or
about 1 .mu.g to about 20 .mu.g, or about 1 .mu.g to about 10
.mu.g, or about 1 to about 5 .mu.g. In aspects, the first polymer
comprises as weight of the biocompatible polymer matrix: about 3
.mu.g to about 5 .mu.g, about 11 .mu.g to about 15 .mu.g, or about
15 .mu.g to about 16 .mu.g, or about 16 to about 17 .mu.g, or about
35 .mu.g to about 53 .mu.g, In aspects, the first polymer is a PEG
polymer. In aspects, the PEG polymer is PEG 3,350. In aspects, the
PEG polymer (e.g., PEG 3,350) can be present as the sole polymer in
the biocompatible polymer matrix. In aspects, the PEG polymer
(e.g., PEG 3,350) can be present in a mixture of polymers in the
biocompatible polymer matrix.
[0018] In certain embodiments, the biocompatible polymer matrix is
comprised of a second polymer. In aspects, the second polymer
comprises as a % w/w of the biocompatible polymer matrix: about 1%
to about 100%, or about 1% to about 90% w/w, or about 1% to about
80%, or about 1% to about 70%, or about 1% to about 60%, or about
1% to about 50%, or about 1% to about 40%, or about 1% to about
30%, or about 1% to about 20%, or about 1% to about 15%, or about
1% to about 10%, or about 1% to about 5%. In aspects, the second
polymer is a PEG polymer. In aspects, the PEG polymer is PEG
100,000. In aspects, the PEG polymer (e.g., PEG 100,000) can be
present as the sole polymer in the biocompatible polymer matrix. In
aspects, the PEG polymer (e.g., PEG 100,000) can be present in a
mixture of polymers in the biocompatible polymer matrix.
[0019] In certain embodiments, the biocompatible polymer matrix is
comprised of a second polymer. In aspects, the second polymer
comprises as weight of the biocompatible polymer matrix: about 1
.mu.g to about 1,000 .mu.g, about 1 .mu.g to about 500 .mu.g, or
about 1 .mu.g to about 400 .mu.g, or about 1 .mu.g to about 300
.mu.g, or about 1 .mu.g to about 200 .mu.g or about 1 .mu.g to
about 100 .mu.g, or about 1 .mu.g to about 50 .mu.g or about 1
.mu.g to about 40 .mu.g, or about 1 .mu.g to about 30 .mu.g, or
about 1 .mu.g to about 20 .mu.g, or about 1 .mu.g to about 10
.mu.g, or about 1 to about 5 .mu.g. In aspects, the second polymer
comprises as weight of the biocompatible polymer matrix: about 26
.mu.g to about 34 .mu.g, or about 92 .mu.g to about 121 .mu.g,
about 121 .mu.g to about 128 .mu.gs, or about 131 .mu.g to about
136 .mu.g, or about 284 to about 430 .mu.g. In aspects, the second
polymer is a PEG polymer. In aspects, the PEG polymer is PEG
100,000. In aspects, the PEG polymer (e.g., PEG 100,000) can be
present as the sole polymer in the biocompatible polymer matrix. In
aspects, the PEG polymer (e.g., PEG 100,000) can be present in a
mixture of polymers in the biocompatible polymer matrix.
[0020] In certain embodiments, the biocompatible polymer matrix is
comprised of a first polymer and a second polymer. In aspects, the
first polymer and the second polymer comprise as a % w/w ratio of
the biocompatible polymer matrix: about 1%/99% to about 99%/1%, or
about 5%/95% to about 95%/5%, or about 10%/90% to about 90%/10%, or
about 15%/85% to about 85%/15%, or about 20%/80% to about 80%/20%,
or about 25%/75% to about 75%/25%, or about 30%/70% to about
70%/30%, or about 35%/65% to about 65%/35%, or about 40%/60% to
about 60%/40%, or about 45%/55% to about 55%/45%, or about 50%/50%.
In aspects, the first polymer and the second polymer comprises as a
% w/w ratio of the biocompatible polymer matrix: about 11%/89%. In
aspects, the first polymer and the second polymer of PEG polymers.
In aspects, the first polymer is a PEG 3,350 polymer, and the
second polymer is a PEG 100,000 polymer.
[0021] In certain embodiments, the biocompatible polymer matrix is
comprised of a first polymer and a second polymer. In aspects, the
first polymer and the second polymer respectively comprises as a
weight of the biocompatible polymer matrix: about 1 .mu.g to about
1000 .mu.g and about 1 .mu.g to about 1000 .mu.g, or about 1 .mu.g
to about 100 .mu.g and about 500 .mu.g to 1000 .mu.g; about 3 .mu.g
to about 50 .mu.g and about 25 .mu.g to 500 .mu.g; or 3 .mu.g to
about 60 .mu.g and about 25 .mu.g to 500 .mu.g; or about 11 .mu.g
to 15 .mu.g and about 92 .mu.g to about 121 .mu.g; or about 15
.mu.g to about 16 .mu.g and about 121 .mu.g to about 128 .mu.g;
about 16 .mu.g to about 17 .mu.g and about 132 .mu.g to about 135
.mu.g; or about 35 .mu.g to about 53 .mu.g and about 284 .mu.g to
about 427 .mu.g; or about 3 .mu.g to about 4 .mu.g and about 27
.mu.g to about 34 .mu.g.
[0022] In certain embodiments, the pharmaceutical implant comprises
as a biocompatible polymer matrix content: about 1 .mu.g to about
1000 .mu.g to about 1 .mu.g to about 900 .mu.g, or about 1 .mu.g to
about 800 .mu.g, or about 1 .mu.g to about 700 .mu.g, or about 1
.mu.g to about 600 .mu.g, or about 1 .mu.g to about 500 .mu.g, or
about 1 .mu.g to about 450 .mu.g, or about 1 .mu.g to about 400
.mu.g, or about 1 .mu.g to about 350 .mu.g, or about 1 .mu.g to
about 300 .mu.g, or about 1 .mu.g to about 250 .mu.g, or about 1
.mu.g to about 200 .mu.g to about 1 .mu.g to about 150 .mu.g, or
about 1 .mu.g to about 100 .mu.g, or about 1 .mu.g to about 50
.mu.g. In certain embodiments, ocular implant comprises as a
biocompatible polymer matrix content: about 30 .mu.g to about 40
.mu.g, or about 100 .mu.g to about 140 .mu.g, or about 130 .mu.g to
about 150 .mu.g, or about 145 .mu.g to about 155 .mu.g, or about
320 .mu.g to about 480 .mu.g.
[0023] In certain embodiments, the therapeutic agent comprises as a
% w/w of the overall implant pharmaceutical composition: about 1%
to about 90%, or about 1% to about 80%, or about 1% to about 70%,
or about 1% to about 60%, or about 1% to about 55%, or about 1% to
about 50%, or about 1% to about 45%, or about 1% to about 40%, or
about 1% to about 35%, or about 1% to about 30%, or about 1% to
about 25%, or about 1% to about 20%, or about 1% to about 15%, or
about 1% to about 10%, or about 1% to about 5%, or about 5% to
about 90%, or about 5% to about 80%, or about 5% to about 70%, or
about 5% to about 60%, or about 5% to about 55%, or about 5% to
about 50%, or about 5% to about 45%, or about 5% to about 40%, or
about 5% to about 35%, or about 5% to about 30%, or about 5% to
about 25%, or about 5% to about 20%, or about 5% to about 15%, or
about 5% to about 10%, or about 10% t.COPYRGT. about 90%, or about
10% to about 80%, or about 10% to about 70%, or about 10% to about
60%, or about 10% to about 55%, or about 10% to about 50%, or about
10% to about 45%, or about 10% to about 40%, or about 10% to about
35%, or about 10% to about 30%, or about 10% to about 25%, or about
10% to about 20%, or about 10% to about 15%, or about 15% to about
90%, or about 15% to about 80%, or about 15% to about 70%, or about
15% to about 60%, or about 15% to about 55%, or about 15% to about
50%, or about 15% to about 45%, or about 15% to about 40%, or about
15% to about 35%, or about 15% to about 30%, or about 15% to about
25%, or about 15% to about 20%, or about 20% to about 90%, or about
20% to about 80%, or about 20% to about 70%, or about 20% to about
60%, or about 20% to about 55%, or about 20% to about 50%, or about
20% to about 45%, or about 20% to about 40%, or about 20% to about
35%, or about 20% to about 30%, or about 20% to about 25%, or about
30% to about 90%. or about 30% to about 80%, or about 30% to about
70%, or about 30% to about 60%, or about 30% to about 55%, or about
30% to about 50%, or about 30% to about 45%, or about 30% to about
40?, or about 30% to about 35%, or about 40% to about 90%, or about
40% to about 80%, or about 40% to about 70%, or about 40% to about
60%, or about 40% to about 55%, or about 40% to about 50%, or about
40% to about 45%, or about 45% to about 90%, or about 45% to about
80%, or about 45% to about 75%, or about 45% to about 70%, or about
45% to about 65%, or about 45% to about 60%, or about 45% to about
55%, or about 45% to about 50%,or about 50% to about 90%, or about
50%, to about 80%, or about 50% to about 70%, or about 50% to about
60%, or about 50% to about 55%, or about 5% to about 8%, or about
10% to about 15%. or about 15% to about 35%, or about 30% to about
45% or about 40% to about 60%; w/w of the pharmaceutical
composition.
[0024] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
PEG polymers, PEG 3,350 and PEG 100,000. In aspects, the PEG 3,350
is present in an amount of from about 11 .mu.g to about 15 .mu.g
per implant (e.g., about 12 .mu.g to about 14 .mu.g per implant),
and the PEG 100,000 is present in an amount of from about 92 .mu.g
to about 121 .mu.g per implant (e.g., about 99 .mu.g to about 114
.mu.g). In aspects, the implant comprises difluprednate in an
amount of 24 to 56 .mu.g per implant (e.g., 32 to 48 .mu.g per
implant). In some embodiments, the implant is a rod-shaped implant
having dimensions of about 225 .mu.m.times.about 225
.mu.m.times.about 2,925 .mu.m. In aspects, the implant has a volume
of 148,078,125 cubic microns.+-.10%. In aspects, the implant is
sized and structured to allow for administration in a 27 gauge
needle. In aspects, the implant is designed for intracameral
administration.
[0025] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
PEG polymers, PEG 3,350 and PEG 100,000. In aspects, the PEG 3,350
is present in an amount of from about 15 .mu.g to about 16 .mu.g
per implant, and the PEG 100,000 is present in an amount of from
about 121 .mu.g to about 128 .mu.g per implant. In aspects, the
implant comprises difluprednate in an amount of 16 to 24 .mu.g per
implant. In some embodiments, the implant is a rod-shaped implant
having dimensions of about 225 .mu.m.times.about 225
.mu.m.times.about 2,925 .mu.m. In aspects, the implant has a volume
of 148,078,125 cubic microns.+-.10%. In aspects, the implant is
sized and structured to allow for administration in a 27 gauge
needle. In aspects, the implant is designed for intracameral
administration.
[0026] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
PEG polymers, PEG 3,350 and PEG 100,000. In aspects, the PEG 3,350
is present in an amount of from about 16 .mu.g to about 17 .mu.g
per implant, and the PEG 100,000 is present in an amount of from
about 132 .mu.g to about 135 .mu.g per implant. In aspects, the
implant comprises difluprednate in an amount of 8 to 12 .mu.g per
implant. In some embodiments, the implant is a rod-shaped implant
having dimensions of about 225 .mu.m.times.about 225
.mu.m.times.about 2,925 .mu.m. In aspects, the implant has a volume
of 148,078,125 cubic microns 10%. In aspects, the implant is sized
and structured to allow for administration in a 27 gauge needle. In
aspects, the implant is designed for intra.cameral
administration.
[0027] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
PEG-polymers, PEG 3,350 and PEG 100,000. In aspects, the PEG 3,350
is present in an amount of from about g to about 53 .mu.g per
implant, and the PEG 100,000 is present in an amount of from about
285 .mu.g to about 427 .mu.g per implant. In aspects, the implant
comprises difluprednate in an amount of 320 to 480 .mu.g per
implant. In some embodiments, the implant is a rod-shaped implant
having dimensions of about 300 .mu.m.times.about 300
.mu.m.times.about 6,000 .mu.m. In aspects, the implant has a volume
of 540,000,000 cubic microns.+-.10%. In aspects, the implant is
sized and structured to allow for administration in a 21 or 22
gauge needle. In aspects, the implant is designed for intracameral
administration.
[0028] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
PEG polymers, PEG 3,350 and PEG 100,000. In aspects, the PEG 3,350
is present in an amount of from about 3 .mu.g to about 4 .mu.g per
implant, and the PEG 100,000 is present in an amount of from about
27 .mu.g to about 34 .mu.g per implant. In aspects, the implant
comprises difluprednate in an amount of 16 to 24 .mu.g per implant.
In some embodiments, the implant is a rod-shaped implant having
dimensions of about 300 .mu.m.times.about 300 .mu.m.times.about
6,000 .mu.m. In aspects, the implant has a volume of 540,000,000
cubic microns.+-.10%. In aspects, the implant is sized and
structured to allow for administration in a 21 or 22 gauge needle.
In aspects, the implant is designed for intracameral
administration.
[0029] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
about 40% to about 60% w/w of the overall implant.
[0030] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
about 65% to about 85% w/w of the overall implant.
[0031] In some embodiments, the at least one therapeutic agent is
selected from the group consisting of: a corticosteroid, steroid,
NSAID, allergy treatment medications, pain treatment medication, or
pharmaceutically acceptable salts thereof, and mixtures thereof, as
well as biologics and other medications for treating or preventing
conditions of the eye.
[0032] In particular embodiments, the at least one therapeutic
agent is selected from the group consisting of: dexamethasone,
fluticasone, loteprednol, difluprednate, fluorometholone, and
prednisolone. In other particular embodiments, the at least one
therapeutic agent is selected from the group consisting of:
beclomethasone, betamethasone, dexamethasone, difluprednate,
fluocinolone, fluocinolone acetonide, fluorometholone, fluticasone
propionate, loteprednol, loteprednol eta bonate, fluorometholone,
prednisolone, prednisolone acetate, prednisolone sodium phosphate,
triamcinolone, triamcinolone acetonide, triamcinolone benetonide,
triamcinolone hexacetonide.
[0033] In one embodiment, the at least one therapeutic agent
comprises difluprednate or a pharmaceutically acceptable salt
thereof or the active metabolite thereof.
[0034] In some aspects, the implant degrades in less than 30 days
and provides sustained release of the therapeutic agent for the
less than the 30 days over which the implant is degrading. In some
embodiments, the implant releases a substantially steady state of
the therapeutic agent for more than 25 days, 20 days, 15 days, or
10 days of the 30 days over which the implant is degrading to
regulate a condition of the eye over such time period.
[0035] In some embodiments, however, the implant is designed to
dissolve in less than 10 days, less than 5 days, less than 1 day,
less than 12 hours, less than 8 hours, less than 4 hours, less than
1 hour, or less than 30 minutes.
[0036] In some aspects, the biocompatible implant substantially
dissolves immediately upon administration to the eye of a patient
(either via intracameral or subconjunctival administration) and the
therapeutic agent is released into the eye upon said dissolution of
the implant and is available to treat the eye for an extended
period of at least about 2-10 days, or about 2-14 days, or about
2-28 days, or about 25-35 days, or about 26-34 days, or about 27-33
days, or about 28 days.
[0037] In some embodiments, the implant is formulated to reduce
post-operative intraocular pressure (IOP) in a patient in need
thereof for at least 1 day, or at least 5 days, or at least 10
days, or at least 15 days, or at least 20 days, or at least 25
days, or at least 30 days, or at least 35 days, or at least 40
days, or at least 45 days, or at least 50 days, In embodiments, IOP
is reduced to within about 20%, or about 15%, or about 12.5%, or
about 10%, or about 7.5%, or about 5%, or about 2.5%, or about 1%
of a baseline.
[0038] In some embodiments, after administration of an implant to a
patient in need thereof, intraocular pressure (IOP) is not elevated
by more than 10 mmHg, or more than 9 mmHg, or more than 8 mmHg, or
more than 7 mmHg, or more than 6 mmHg, or more than 5 mmHg, or more
than 4 mmHg, or more than 3 mmHg, or more than 2 mmHg, or more than
1 mmHg. In some embodiments, after administration of an implant to
a patient in need thereof, intraocular pressure (IOP) is not
elevated by more than 90%, or more than 80%, or more than 70%, or
more than 60%, or more than 50%, or more than 40%, or more than
30%, or more than 20%, or more than 10%, or more than 5% of a
baseline.
[0039] In aspects, pharmacokinetics of the ocular implants
described herein are measured in a rabbit model. In embodiments,
the average for the therapeutic agent or active metabolite thereof
in the plasma is about 80% to about 120% of 0.99-2.75 ng/mL. In
embodiments, the average AUQ.sub.last for the therapeutic agent or
active metabolite thereof in the plasma is about 80% to about 120%
of 0.495-2.44 d*ng/mL. In embodiments, the average C.sub.max for
the therapeutic agent or active metabolite thereof in the aqueous
humor is about 80% to about 120% of 3,420-11,158 ng/mL. In
embodiments, the average AUC.sub.last for the therapeutic agent or
active metabolite thereof in the aqueous humor is about 80% to
about 120% of 3,323-10,427 d*ng/mL. In embodiments, the average
C.sub.max for the therapeutic agent or active metabolite thereof in
the bulbar conjunctiva is about 80% to about 120% of 106-233 ng/mL.
In embodiments, the average AUC.sub.last for the therapeutic agent
or active metabolite thereof in the bulbar conjunctiva is about 80%
to about 120% of 135-716 d*ng/mL. In embodiments, the average
C.sub.max for the therapeutic agent or active metabolite thereof in
the cornea is about 80% to about 120% of 11,283-39,875 ng/mL. In
embodiments, the average AUC.sub.last for the therapeutic agent or
active metabolite thereof in the cornea is about 80% to about 120%
of 9,329-33,262 d*ng/mL. In embodiments, the average C.sub.max for
the therapeutic agent or active metabolite thereof in the
trabecular meshwork is about 80% to about 120% of 9,435-24,825
ng/mL. In embodiments, the average AUC.sub.last for the therapeutic
agent or active metabolite thereof in the trabecular meshwork is
about 80% to about 120% of 8,571-29,174 d*ng/mL. In embodiments,
the average C.sub.max for the therapeutic agent or active
metabolite thereof in the iris/ciliary body is about 80% to about
120% of 13,115-41,700 ng/mL. In embodiments, the average
AUC.sub.last for the therapeutic agent or active metabolite thereof
in the iris/ciliary body is about 80% to about 120% of
13,174-49,403 d*ng/mL. In embodiments, the average C.sub.max for
the therapeutic agent or active metabolite thereof in the retina is
about 80% to about 120% of 89.9-92.1. In embodiments, the average
AUC.sub.last for the therapeutic agent or active metabolite thereof
in the retina is about 80% to about 120% of d*222-764 ng/mL.
[0040] In certain embodiments, the implants are able to reduce
post-operative corneal thickening by about 1%, or about 5%, or
about 10%, or about 20%, or about 30%, or about 40%, or about 50%,
or about 60%, or about 70%, or about 80%, or about 90%, or about
100%. In embodiments, the implants described herein are able to
reduce post-operation corneal thickening in the range of from about
1% to about 100%, or about, or about 5% to about 100%, or about 10%
to about 100%, or about 20% to about 100%, or about 30% to about
100%, or about 40% to about 100%, or about 50% to about 100%, or
about 60% to about 100%, or about 70% to about 100%, or about 80%
to about 100%, or about 90% to about 100%.
[0041] In other embodiments, the implants described herein are able
to reduce post-surgery corneal thickening below a baseline
established prior to surgery by about 1% to about 100%, or about,
or about 1% to about 90%, or about 1% to about 80%, or about 1% to
about 70%, or about 1% to about 60%, or about 1% to about 50%, or
about 1% to about 40%, or about 1% to about 30%, or about 1% to
about 20%, or about 1% to about 10%, or about 1% to about 5%, or 1%
or more, or about 5% or more, or about 10% or more, or about 20% or
more, or about 30% or more, or about 40% or more, or about 50% or
more.
[0042] In some embodiments, the implants described herein are able
to reduce corneal thickness to or below a baseline within about 30
days or less, e.g., less than or equal to about 25 days, or less
than or equal to 20 days, or less than or equal to 15 days, or less
than or equal to 10 days, or less than or equal to 7 days, or less
than or equal to 6 days, or less than or equal to 5 days, or less
than or equal to 4 days, or less than or equal to 3 days, or less
than or equal to 2 days, or less than or equal to 1 days.
Therefore, in some embodiments, the implants described herein can
reduce surgery-induced cortical thickening to or below a baseline
within about 1 day after administration of said implant.
[0043] In some embodiments, the reduction in corneal thickening
comprises as a percent change from a baseline: about 1%, or about
2%, or about 3%, or about 4%, or about 5%, or about 6%, or about
7%, or about 8%, or about 9%, or about 10%. In embodiments, the
reduction in corneal thickening comprises as a percent change from
baseline of from about 1% to about 20%, or from about 1% to about
15%, or from about 1% to about 10%, or from about 1% to about 9%,
or from about 1% to about 8%, or from about 1% to about 7%, or from
about 1% to about 6%, or form about 1% to about 6%, or from about
1% to about 5%, or from about 1% to about 4%, or from about 1% to
about 3%, or from about 1% to about 2%.
[0044] In embodiments disclosed herein is an extended treatment
rapid delivery system for treating post-operative ocular
inflammation in an eye of a patient in need thereof, comprising: A)
a biocompatible polymer matrix based ocular implant rapid delivery
vehicle; and B) at least one therapeutic agent homogeneously
dispersed within the polymer matrix, wherein said ocular implant
rapid delivery vehicle is formulated to reduce corneal thickening
which is associated with administration of an implant.
[0045] In embodiments which entail formulating an implant to reduce
corneal thickening which is associated with administration of an
implant, the amount of polymer matrix per implant is less than
about 500 .mu.g, or less than about 400 .mu.g, or less than about
300 .mu.g, or less than about 200 .mu.g, or less than about 150
.mu.g, or less than about 140 .mu.g, or less than about 130 .mu.g,
or less than about 120 .mu.g, or less than about 110 .mu.g, or less
than about 100 .mu.g, or less than about 90 .mu.g, or less than
about 80 .mu.g, or less than about 70 .mu.g, or less than about 60
.mu.g, or less than about 50 .mu.g, or less than about 40 .mu.g, or
less than about 30 .mu.g, or less than about 20 .mu.g, or less than
about 10 .mu.g. In embodiments, the implant comprises a polymer
matrix content of from about 10 .mu.g to about 100 .mu.g, or about
10 .mu.g to about 90 .mu.g, or about 10 .mu.g to about 80 .mu.g, or
about 10 .mu.g to about 70 .mu.g, or about 10 .mu.g to about 60
.mu.g, or about 10 .mu.g to about 50 .mu.g, or about 10 .mu.g to
about 40 .mu.g, or about 10 .mu.g to about 30 .mu.g, or about 10
.mu.g to about 20 .mu.g.
[0046] In some embodiments which entail formulating an implant to
reduce corneal thickening which is associated with administration
of a hydrophilic implant, the reduction in corneal thickening can
be achieved by decreasing the percent weight ratio (% w/w) of the
polymer matrix relative to the therapeutic agent. In embodiments,
the percent weight ratio (% w/w) of the polymer matrix relative to
the therapeutic agent is from about 20% to about 95%, or from about
20% to about 90%, or from about 20% to about 85%, or from about 20%
to about 80%, or from about 20% to about 75%, or from about 20% to
about 70%, or form about 20% to about 65%, or from about 20% to
about 60%, or from about 20% to about 55%, or from about 20% to
about 50%, or from about 20% to about 45%, or from about 20% to
about 40%, or from about 20% to about 35%, or 30% to about 85%, or
from about 30% to about 80%, or from about 30% to about 75%, or
from about 30% to about 70%, or form about 30% to about 65%, or
from about 30% to about 60%, or from about 30% to about 55%, or
from about 30% to about 50%, or from about 30% to about 45%, or
from about 30% to about 40%, or from about 30% to about 35%.
[0047] In aspects, pharmacokinetics of the ocular implants
described herein are measured in a rabbit model. In embodiments,
the average C.sub.max for the therapeutic agent or active
metabolite thereof in the plasma is about 80% to about 120% of
0.99-2.75 ng/mL. In embodiments, the average AUC.sub.last for the
therapeutic agent or active metabolite thereof in the plasma is
about 80% to about 120% of 0.495-2.44 ng/mL. In embodiments, the
average C.sub.max for the therapeutic agent or active metabolite
thereof in the aqueous humor is about 80% to about 120% of
3,420-11,158 ng/mL. In embodiments, the average AUC.sub.last for
the therapeutic agent or active metabolite thereof in the aqueous
humor is about 80% to about 120% of 3,323-10,427 ng/mL. In
embodiments, the average C.sub.max for the therapeutic agent or
active metabolite thereof in the bulbar conjunctiva is about 80% to
about 120% of 106-233 ng/mL. In embodiments, the average
AUC.sub.last for the therapeutic agent or active metabolite thereof
in the bulbar conjunctiva is about 80% to about 120% of 135-716
ng/mL. In embodiments, the average C.sub.max for the therapeutic
agent or active metabolite thereof in the cornea is about 80% to
about 120% of 11,283-39,875 ng/mL. In embodiments, the average
AUC.sub.last for the therapeutic agent or active metabolite thereof
in the cornea is about 80% to about 120% of 9,329-33,262 ng/mL. In
embodiments, the average C.sub.max for the therapeutic agent or
active metabolite thereof in the trabecular meshwork is about 80%
to about 120% of 9,435-24,825 ng/mL. In embodiments, the average
AUC.sub.last for the therapeutic agent or active metabolite thereof
in the trabecular meshwork is about 80% to about 120% of
8,571-29,174 ng/mL. In embodiments, the average C.sub.max for the
therapeutic agent or active metabolite thereof in the iris/ciliary
body is about 80% to about 120% of 13,115-41,700 ng/mL. In
embodiments, the average AUC.sub.last for the therapeutic agent or
active metabolite thereof in the iris/ciliary body is about 80% to
about 120% of 13,174-49,403 ng/mL. In embodiments, the average
C.sub.max for the therapeutic agent or active metabolite thereof in
the retina is about 80% to about 120% of 89.9-92.1 ng/mL. In
embodiments, the average AUC.sub.last for the therapeutic agent or
active metabolite thereof in the retina is about 80% to about 120%
of 222-764 ng/mL.
[0048] In some embodiments, the ocular implant is a rod-shaped
implant comprising a shortest dimension of between about 100 to
about 500 .mu.m and a longest dimension of between about 2,000 to
about 8,000 .mu.m in length.
[0049] In other embodiments, the ocular implant has an aspect ratio
of width to length of between 1:2 and 1:40.
[0050] In some embodiments, the implant is a rod-shaped implant
selected from the group consisting of: a rod-shaped implant having
dimensions of about 225 .mu.m.times.about 225 .mu.m.times.about
3,000 .mu.m, a rod-shaped implant having dimensions of about 225
.mu.m.times.about 225 .mu.m.times.about 4,000 .mu.m, a rod-shaped
implant having dimensions of about 300 .mu.m.times.about 300
.mu.m.times.about 6,000 .mu.m, a rod-shaped implant having
dimensions of about 400 .mu.m.times.about 400 .mu.m.times.about
6,000 .mu.m, and a rod-shaped implant having dimensions of about
130 .mu.m.times.about 180 .mu.m.times.about 1,500 .mu.m.
[0051] In some embodiments, the implant is a rod-shaped implant
having dimensions of about 130.mu.m.times.about 180
.mu.m.times.about 1,500 .mu.m. In some embodiments, the implant has
dimensions within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%,
or 0.1% of the aforementioned 130 .mu.m.times.about 180
.mu.m.times.about 1,500 .mu.m.
[0052] In some embodiments, the implant is a rod-shaped implant
having dimensions of about 225 .mu.m.times.about 225
.mu.m.times.about 2,925 .mu.m. In some embodiments, the implant has
dimensions within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%,
or 0.1% of the aforementioned 225 .mu.m.times.about 225
.mu.m.times.about 2,925 .mu.m.
[0053] In some embodiments, the implant is a rod-shaped implant
having dimensions of about 330 .mu.m.times.about 330
.mu.m.times.about 6,000 .mu.m. In some embodiments, the implant has
dimensions within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%,
or 0.1% of the aforementioned 330 .mu.m.times.about 330
.mu.m.times.about 6,000 .mu.m.
[0054] In some embodiments, the implant is a rod-shaped implant
having dimensions of about 300 .mu.m.times.about 300
.mu.m.times.about 6,000 .mu.m. In some embodiments, the implant has
dimensions within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%,
or 0.1% of the aforementioned 300 .mu..mu.m.times.about 300
.mu.m.times.about 6,000 .mu.m.
[0055] Further still, are disclosed pharmaceutical compositions for
treating an ocular condition, comprising: A) a biocompatible
polymer matrix; and B) at least one therapeutic agent homogenously
dispersed within the polymer matrix. Another embodiment disclosed
herein is a pharmaceutical composition for treating an ocular
condition, comprising: a biocompatible implant comprising at least
one polymer; and a therapeutic agent homogenously dispersed within
the at least one polymer; wherein the implant comprises: a length
within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1% of
2,925 microns; a width within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%,
0.5%, 0.25%, 0.1% of 225 microns; and a height within 10%, 7.5%,
5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1% of 225 microns.
[0056] Another embodiment disclosed herein is a pharmaceutical
composition for treating an ocular condition, comprising: a
biocompatible implant comprising at least one polymer; and a
therapeutic agent homogenously dispersed within the at least one
polymer; wherein the implant comprises: a length within 10%, 7.5%,
5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1% of 6,000 microns; a width
within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1% of 330
microns; and a height within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%,
0.5%, 0.25%, 0.1% of 330 microns.
[0057] Another embodiment disclosed herein is a pharmaceutical
composition for treating an ocular condition, comprising: a
biocompatible implant comprising at least one polymer; and a
therapeutic agent homogenously dispersed within the at least one
polymer; wherein the implant comprises: a length within 10%, 7.5%,
2.5%. 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1% of 6,000 microns; a width
within 10%. 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1% of 300
microns; and a height within 10%, 7.5% 5%, 2.5%, 2%, 1.5%, 1%,
0.5%, 0.25%, 0.1% of 300 microns.
[0058] Another embodiment disclosed herein is a pharmaceutical
composition for treating an ocular condition, comprising: a
biocompatible implant comprising at least one polymer; and a
therapeutic agent homogenously dispersed within the at least one
polymer; wherein the implant comprises: a length within 10%, 7.5%,
5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1% of 1.500 microns; a width
within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.7.5%, 0.1% of 130
microns; and a height within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%,
0.5%, 0.25%, 0.1% of 180 microns.
[0059] In certain embodiments, the disclosure presents a
pharmaceutical composition for treating an ocular condition,
comprising: a biocompatible implant comprising at least one
polymer; and a therapeutic agent homogenously dispersed within the
at least one polymer; wherein the implant comprises: a length
within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.75%, 0.1% of
4,000 microns; a width within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%,
0.5%, 0.25%, 0.1% of 225 microns; and a height within 10%, 7.5%,
5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1% of 225 microns.
[0060] In another aspect, taught herein is a pharmaceutical
composition for treating an ocular condition, comprising: a
biocompatible implant comprising at least one polymer; and a
therapeutic agent homogenously dispersed within the at least one
polymer; wherein the implant comprises: a length within 10%, 7.5%,
5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1% of 6,000 microns; a width
within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1% of 400
microns; and a height within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%,
0.5%, 0.25%, 0.1% of 400 microns.
[0061] In other embodiments, the disclosure provides a
pharmaceutical composition for treating an ocular condition,
comprising: a biocompatible implant comprising at least one
polymer; and a therapeutic agent homogenously dispersed within the
at least one polymer; wherein the implant comprises: a therapeutic
agent weight percent within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%,
0.5%, 0.25%, 0.1% of 25% of the implant overall weight; a weight
percent of the at least one polymer within 10%, 7.5%, 5%, 2.5%, 2%,
1.5%, 1%, 0.5%. 0.25%, 0.1% of 75% of the implant overall
weight.
[0062] In other embodiments, the disclosure provides a
pharmaceutical composition fbr treating an ocular condition,
comprising: a biocompatible implant comprising at least one
polymer; and a therapeutic agent homogenously dispersed within the
at least one polymer; wherein the implant comprises: a therapeutic
agent weight percent within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%,
0.5%, 0.25%, 0.1% of 50% of the implant overall weight; a weight
percent of the at least one polymer within 10%, 7.5%, 5%, 2.5%, 2%,
1.5%, 1%, 0.5%, 0.7.5%, 0.1% of 50% of the implant overall
weight.
[0063] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
about 65% to about 85% w/w of the overall implant (e.g., about 70%
to about 80% w/w) and the therapeutic agent comprises about 15% to
about 35% w/w of the overall implant (e.g., about 20% to about 30%
w/w). In aspects, the therapeutic agent is difluprednate and the
polymer matrix comprises PEG polymers. In aspects, the PEG polymers
are PEG 3,350 and PEG 100,000. In aspects, the ratio of PEG 3,350
to PEG 100,000 is 11%/89%. In some embodiments, the implant is a
rod-shaped implant having dimensions of about 225 .mu.m.times.about
225 .mu.m.times.about 2,925 .mu.m. In aspects, the implant
comprises difluprednate in an amount of 24 to 56 .mu.g per implant
(e.g., 32 to 48 .mu.g per implant). In aspects, the implant has a
volume of 148,078,125 cubic microns.+-.10%. In aspects, the implant
is sized and structured to allow for administration in a 27 gauge
needle. In aspects, the implant is designed for intracameral
administration.
[0064] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
about 40% to about 60% w/w of the overall implant and the
therapeutic agent comprises about 40% to about 60% wiw of the
overall implant. In aspects, the therapeutic agent is difluprednate
and the polymer matrix comprises PEG polymers. In aspects, the PEG
polymers are PEG 3,350 and PEG 100,000. In aspects, the ratio of
PEG 3,350 to PEG 100,000 is 11%/89%. In some embodiments, the
implant is a rod-shaped implant having dimensions of about 300
.mu.m.times.about 300 .mu.m.times.about 6,000 .mu.m. In aspects,
the implant comprises difluprednate in an amount of 640 to 960
.mu.g per implant. In aspects, the implant has a volume of
540,000,000 cubic microns.+-.10%. In aspects, the implant is sized
and structured to allow for administration in a 21 gauge needle or
a 22 gauge needle. In aspects, the implant is designed for
subconjunctival administration.
[0065] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
about 40% to about 60% w/w of the overall implant and the
therapeutic agent comprises about 40% to about 60% w/w of the
overall implant. In aspects, the therapeutic agent is difluprednate
and the polymer matrix comprises PEG polymers. In aspects, the PEG
polymers are PEG 3,350 and PEG 100,000. In aspects, the ratio of
PEG 3,350 to PEG 100,000 is 11%/89%. In some embodiments, the
implant is a rod-shaped implant having dimensions of about 330
.mu.m.times.about 330 .mu.m.times.about 6,000 .mu.m. In aspects,
the implant comprises difluprednate in an amount of 320 to 480
.mu.g per implant. In aspects, the implant has a volume of
653,400,000 cubic microns.+-.10%.
[0066] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
about 40% to about 60% w/w of the overall implant and the
therapeutic agent comprises about 40% to about 60% w/w of the
overall implant. In aspects, the therapeutic agent is difluprednate
and the polymer matrix comprises PEG polymers. In aspects, the PEG
polymers are PEG 3,350 and PEG 100,000. In aspects, the ratio of
PEG 3,350 to PEG 100,000 is 11%/89%. In some embodiments, the
implant is a rod-shaped implant having dimensions of about 300
.mu.m.times.about 300 .mu.m.times.about 6,000 .mu.m. In aspects,
the implant comprises difluprednate in an amount of 320 to 480
.mu.g per implant. In aspects, the implant has a volume of
540,000,000 cubic microns.+-.10%.
[0067] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
about 85% to about 90% w/w of the overall implant and the
therapeutic agent comprises about 10% to about 15% w/w of the
overall implant. In aspects, the therapeutic agent is difluprednate
and the polymer matrix comprises PEG polymers. In aspects, the PEG
polymers are PEG 3,350 and PEG 100,000. In aspects, the ratio of
PEG 3,350 to PEG 100,000 is 11%/89%. In some embodiments, the
implant is a rod-shaped implant having dimensions of about 225
.mu.m.times.about 225 .mu.m.times.about 2,925 .mu.m. In aspects,
the implant comprises difluprednate in an amount of 16 to 24 .mu.g
per implant. In aspects, the implant has a volume of 148,078,125
cubic microns.+-.10%. In aspects, the implant is sized and
structured to allow for administration in a 27 gauge needle. In
aspects, the implant is designed for intracameral
administration.
[0068] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
about 92.5% to about 95% w/w of the overall implant and the
therapeutic agent comprises about 5% to about 7.5% w/w of the
overall implant. In aspects, the therapeutic agent is difluprednate
and the polymer matrix comprises PEG polymers. In aspects, the PEG
polymers are PEG 3,350 and PEG 100,000. In aspects, the ratio of
PEG 3,350 to PEG 100,000 is 11%/89%. In some embodiments, the
implant is a rod-shaped implant having dimensions of about 225
.mu.m.times.about 225 .mu.m.times.about 2,925 .mu.m. In aspects,
the implant comprises difluprednate in an amount of 8 to 12 .mu.g
per implant. In aspects, the implant has a volume of 148,078,125
cubic microns.+-.10%. In aspects, the implant is sized and
structured to allow for administration in a 27 gauge needle. In
aspects, the implant is designed for intracameral
administration.
[0069] In certain embodiments, the disclosure provides for an
ocular implant comprising: A) a biocompatible polymer matrix; and
B) at least one therapeutic agent homogenously dispersed within the
polymer matrix, wherein the biocompatible polymer matrix comprises
about 55% to about 70% w/w of the overall implant and the
therapeutic agent comprises about 30% to about 45% w/w of the
overall implant. In aspects, the therapeutic agent is difluprednate
and the polymer matrix comprises PEG polymers. In aspects, the PEG
polymers are PEG 3,350 and PEG 100,000. In aspects, the ratio of
PEG 3,350 to PEG 100,000 is 11%/89%. In some embodiments, the
implant is a rod-shaped implant having dimensions of about 130
.mu.m.times.about 180 .mu.m.times.about 1,500 .mu.m. In aspects,
the implant comprises difluprednate in an amount of 16 to 24 .mu.g
per implant. In aspects, the implant has a volume of 35,100,000
cubic microns.+-.10%. In aspects, the implant is sized and
structured to allow for administration in a 25, 26, or 27 gauge
needle. In aspects, the implant is designed for intracameral
administration.
[0070] In an aspect, one, two, three, four, five, six, seven,
eight, nine, or more implants are provided in the method and
implanted. The plurality of implants may be implanted
simultaneously into the eye of a patient, sequentially during the
same procedure, or sequentially over a period of time during
different procedures. In some aspects, a patient receives periodic
implants such as weekly, monthly, bimonthly, quarterly,
semi-annual, or yearly implants.
[0071] Another embodiment provided herein is a method for treating
or preventing an ocular condition, comprising: implanting at least
one implant into an eye of a patient in need of treatment wherein
each implant has a volume within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%,
0.5%, 0.25%, 0.1% of 202,500,000 cubic microns.
[0072] Also provided is a method for treating or preventing an
ocular condition, comprising: implanting at least one implant into
an eye of a patient in need of treatment wherein each implant has a
volume within 10%, 7.5%, 5%, 1%, 0.5%, 0.25%, 0.1% of 960,000,000
cubic microns.
[0073] Also provided is a method for treating or preventing an
ocular condition, comprising: implanting at least one implant into
an eye of a patient in need of treatment wherein each implant has a
volume within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1%
of 148,078,125 cubic microns.
[0074] Also provided is a method for treating or preventing an
ocular condition, comprising: implanting at least one implant into
an eye of a patient in need of treatment wherein each implant has a
volume within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1%
of 653,400,000 cubic microns.
[0075] Another embodiment provides a method for treating or
preventing an ocular condition, comprising: implanting at least one
implant into an eye of a patient in need of treatment wherein each
implant has a volume within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%,
0.5%, 0.25%, 0.1% of 540,000,000 cubic microns.
[0076] Another embodiment provides a method for treating or
preventing an ocular condition, comprising: implanting at least one
implant into an eye of a patient in need of treatment wherein each
implant has a volume within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%,
0.5%, 0.25%, 0.1% of 35,100,000 cubic microns.
[0077] In an aspect, the disclosure provides a method for
preventing or treating post-operative inflammation and/or pain in
an eye of a patient in need of treatment comprising: inserting at
least one implant having a volume within 10%, 7.5%, 5%, 2.5%, 2%,
1.5%, 1%, 0.5%, 0.25%, 0.1% of 202,500,000 cubic microns and
therapeutic agent content between about 20 wt % and about 55 wt %;
or inserting at least one implant, having a volume within 10%,
7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1% of 540,000,000
cubic microns and therapeutic agent content between about 25 wt %
and about 55 wt %; or inserting at least one implant, having a
volume within 10%, 7.5%, 5%, 7.5%, 7%, 1.5%, 1%, 0.5%, 0.25%, 0.1%
of 960,000,000 cubic microns and therapeutic agent content between
about 25 wt % and about 45 wt %; or inserting at least one implant,
having a volume within 10%, 7.5%, 5%, 2.5%, 7%, 1.5%, 1%, 0.5%,
0.25%, 0.1% of 148,078,125 cubic microns and therapeutic agent
content between about 15 wt % to about 35 wt %, about 10 wt % to
about 15 wt %, or about 5 wt % to about 7.5 wt %; or inserting at
least one implant, having a volume within 10%, 7.5%, 5%, 2.5%, 2%,
5%, 1%, 0.5%, 0..sup.75%, 0.1% of 653,400,000 cubic microns, or
540,000,000 cubic microns, and therapeutic agent content between
about 40 wt % to about 60 wt %; or inserting at least one implant,
having a volume within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%,
0.25%, 0.1% of 35,100,000 cubic microns and therapeutic agent
content between about 29.6 wt % and about 44.4 wt %. In aspects,
the post-operative inflammation and/or pain is managed for at least
2 days following insertion into the subconjunctival, or
intracameral, region of the eye.
[0078] In an aspect, the disclosure provides a method for
preventing or treating post-operative inflammation and/or pain in
an eye of a patient undergoing an ocular surgical procedure, or who
has undergone an ocular surgical procedure, comprising: inserting
at least one implant having a volume within 10%, 7.5%, 5%, 2.5%,
2%, 1.5%, 1%, 0.5%, 0.75%, 0.1% of 202,500,000 cubic microns and
therapeutic agent content between about 20 wt % and about 55 wt %;
or inserting at least one implant, having a volume within 10%,
7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1% of 540,000,000
cubic microns and therapeutic agent content between about 25 wt %
and about 55 wt %; or inserting at least one implant, having a
volume within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.25%, 0.1%
of 960,000,000 cubic microns and therapeutic agent content between
about 25 wt % and about 45 wt %; or inserting at least one implant,
having a volume within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%,
0.25%, 0.1% of 148,078,125 cubic microns and therapeutic agent
content between about 15 wt % to about 35 wt %, about 10 wt % to
about 15 wt %, or about 5 wt % to about 7.5 wt %; or inserting at
least one implant, having a volume within 10%, 7.5%, 5%, 2.5%, 2%,
1.5%, 1%, 0.5%, 0.25%, 0.1% of 653,400,000 cubic microns, or
540,000,000 cubic microns, and therapeutic agent content between
about 40 wt % to about 60 wt %; or inserting at least one implant,
having a volume within 10%, 7.5%, 5%, 2.5%, 2%, 1.5%, 1%, 0.5%,
0.25%, 0.1% of 35,100,000 cubic microns and therapeutic agent
content between about 29.6 wt % and about 44.4 wt %. In aspects,
the post-operative inflammation and/or pain is managed for at least
2 days following insertion into the subconjunctival, or
intracameral, region of the eye.
[0079] In embodiments, implants may have a volume of 35,100,000
cubic microns, 202,500,000 cubic microns, or 540,000,000 cubic
microns, or 960,000,000 cubic microns, or 148,078,125 cubic
microns, or 653,400,000 cubic microns. In some embodiments, the
volume from implant to implant may vary by about 0.1% to about 10%.
The disclosure provides for compositions comprising the implants,
kits comprising the implants, methods of utilizing the
aforementioned implants, and systems comprising the implants with
the stated cubic micron volumes.
[0080] In certain embodiments, the aforementioned polymer matrix
excludes other polymers from being present in the composition. For
instance, in some aspects PLGA is not present. In other aspects,
the aforementioned implants only comprise PEG polymers and exclude
other polymers from being present. In some embodiments, hot melt
extrusion is not used to fabricate the implants. In some
embodiments, in-situ gelation is not utilized to fabricate the
implants.
[0081] In certain embodiments, the pharmaceutical formulations
exclude implants that are not of the following volumes:
202,500,000.+-.10% cubic microns, or 540,000,000.+-.10% cubic
microns, or 960,000,000.+-.10% cubic microns, or 148,078,125.+-.10%
cubic microns, or 653,400,000.+-.10% cubic microns, or
35,100,00.+-.10% cubic microns. Some embodiments exclude implants
that are not of the following dimensions: about 130
.mu.m.times.about 180 .mu.m.times.about 1,500 .mu.m; about 225
.mu.m.times.about 225 .mu.m.times.about 4,000 .mu.m, or about 300
.mu.m.times.about 300 .mu.m.times.about 6,000 .mu.m, or about 400
.mu.m.times.about 400 .mu.m.times.about 6,000 .mu.m, or about 225
.mu.m.times.about 225 .mu.m.times.about 2,925 .mu.m, or about 330
.mu.m.times.about 330 .mu.m.times.about 6,000 .mu.m. Some
embodiments taught herein exclude implants that are not fabricated
in a mold based method, such as for example by PRINT.RTM.
technology fabrication.
[0082] In some aspects, the disclosure provides a method of
prevention and/or treatment of post-operative inflammation and/or
pain, in a human subject by administering via subconjunctival
injection, or intracameral injection a solid, biocompatible,
rod-shaped subconjunctival, or intracameral., implant to the
subject.
[0083] In a particular aspect, the implants of the disclosure do
not migrate substantially from their initial position. In other
aspects, the implants may move substantially from their initial
position,
[0084] In embodiments of the disclosed methods, post-operative
inflammation in a human is controlled for at least 2 days, or 7
days, or 10 days, or 14 days, or 20 days, or 24 days, or in aspects
at least 28 days, following implantation of at least one implant,
via subconjunctival injection, or intracameral injection, to the
eye of a patient. The implants may comprise a therapeutic agent
content ranging from about: 1 to 1200 .mu.g per implant, 1 to 1000
.mu.g per implant, 1 to 800 .mu.g per implant, 1 to 500 .mu.g per
implant, 1 to 400 .mu.g per implant, 1 to 300 .mu.g per implant, 1
to 200 .mu.g per implant, 1 to 150 .mu.g per implant, 1 to 140
.mu.g per implant, 1 to 130 .mu.g per implant, 1 to 120 .mu.g per
implant, 1 to 110 .mu.g per implant, 1 to 100 .mu.g per implant, 1
to 90 .mu.g per implant, 1 to 80 .mu.g per implant, 1 to 70 .mu.g
per implant, 1 to 60 .mu.g per implant, 1 to 50 .mu.g per implant,
1 to 40 .mu.g per implant, 1 to 30 .mu.g per implant, 1 to 20 .mu.g
per implant, 1 to 10 .mu.g per implant, or 1 to 8 .mu.g per
implant. The implants may comprise therapeutic agent content
ranging from about: about 8 to about 480 .mu.g per implant, about 8
to about 12 .mu.g per implant, about 16 to about 24 .mu.g per
implant, about 32 to 48 .mu.g per implant, about 24 to about 56
.mu.g per implant, or about 320 to about 480 .mu.g per implant. In
some embodiments, the drug is difluprednate. It should be
appreciated that the dose of the therapeutic agent in a given
implant composition may be selected to be between the ranges given
herein; however, once the dose is selected, the dose between
implants for that application is substantially consistent, wherein
the dose between implants varies less than 10%, less than 5%, less
than 2%, less than 1% less than 0.5% or less than 0.1% on a weight
percentage basis.
[0085] In some aspects, an implant formulated for intracameral
placement may comprise a therapeutic agent concentration of about
20 .mu.g to about 60 .mu.g.+-.10 .mu.g per implant, or may comprise
a therapeutic agent concentration of about 24 .mu.g to about 56
.mu.g.+-.10 .mu.g per implant, or may comprise a therapeutic agent
concentration of about 40 .mu.g.+-.10 .mu.g per implant, or may
comprise a therapeutic agent concentration of about 8 .mu.g to
about 56 .mu.g.+-.10 .mu.g per implant, or may comprise a
therapeutic agent concentration of about 8 .mu.g to about 12
.mu.g.+-.10 .mu.g per implant, or may comprise a therapeutic agent
concentration of about 16 .mu.g to about 24 .mu.g.+-.10 .mu.g per
implant, or may comprise a therapeutic agent concentration of about
24 .mu.g to about 56 .mu.g.+-.10 .mu.g per implant.
[0086] In some aspects, an implant formulated for subconjunctival
placement may comprise a therapeutic agent concentration of about
300 .mu.g to about 500 .mu.g.+-.10 .mu.g per implant, or may
comprise a therapeutic agent concentration of about 320 .mu.g to
about 480 .mu.g.+-.10 .mu.g per implant, or may comprise a
therapeutic agent concentration of about 400 .mu.g.+-.10 .mu.g per
implant.
[0087] Also disclosed is a pharmaceutical composition, comprising:
at least one ocular implant, wherein said at least one ocular
implant has a volume of 33,750,000.+-.10% cubic microns; and
comprises: A) a biocompatible polymer matrix; and B) at least one
therapeutic agent homogenously dispersed within the polymer
matrix.
[0088] Further provided by the present disclosure is a
pharmaceutical composition, comprising: at least one ocular
implant, wherein said at least one ocular implant has a volume of
148,078,125.+-.10% cubic microns; and comprises: A) a biocompatible
polymer matrix; and B) at least one therapeutic agent homogenously
dispersed within the polymer matrix.
[0089] Further provided by the present disclosure is a
pharmaceutical composition, comprising: at least one ocular
implant, wherein said at least one ocular implant has a volume of
653,400,000.+-.10% cubic microns; and comprises: A) a biocompatible
polymer matrix; and B) at least one therapeutic agent homogenously
dispersed within the polymer matrix.
[0090] Further provided by the present disclosure is a
pharmaceutical composition, comprising: at least one ocular
implant, wherein said at least one ocular implant has a volume of
540,000,000.+-.10% cubic microns; and comprises: A) a biocompatible
polymer matrix; and B) at least one therapeutic agent homogenously
dispersed within the polymer matrix.
[0091] Some embodiments entail administering one ocular implant
having a volume of 202,500,000.+-.10% cubic microns to an eye.
Other embodiments entail administering two ocular implants each
having a volume of 202,500,000.+-.10% cubic microns to an eye. Yet
other embodiments entail administering three ocular implants each
having a volume of 202,500,000.+-.10% cubic microns to an eye. Yet
other embodiments entail administering three or more ocular
implants each having a volume of 202,500,000.+-.10% cubic microns
to an eye. In some embodiments, each of the aforementioned ocular
implants having a volume of 202,500,000.+-.10% cubic microns
contains a difluprednate content of from 35 .mu.g to 125 .mu.g.
[0092] Some embodiments entail administering one ocular implant
having a volume of 148,078,125.+-.10% cubic microns to an eye.
Other embodiments entail administering two ocular implants each
having a volume of 148,078,125.+-.10% cubic microns to an eye. Yet
other embodiments entail administering three ocular implants each
having a volume of 148,078,125.+-.10% cubic microns to an eye. Yet
other embodiments entail administering three or more ocular
implants each having a volume of 148,078,125.+-.10% cubic microns
to an eye. In sonic embodiments, each of the aforementioned ocular
implants having a volume of 148,078,125.+-.10% cubic microns
contains a difluprednate content of from about 8 .mu.g to about 56
.mu.g. In sonic aspects, the implants comprise about 40 .mu.g
difluprednate. In aspects which entail administering two ocular
implants to an eye, said implants comprise from about 8 .mu.g to
about 56 .mu.g (e.g., about 40 .mu.g) difluprednate per implant,
and the amount of difluprednate administered to the eye is from 16
.mu.g to about 112 .mu.g (e.g., about 80 .mu.g). In aspects which
entail administering three ocular implants to an eye, said implants
comprise from about 8 .mu.g to about 56 .mu.g (e.g., about 40
.mu.g) difluprednate per implant, and the amount of difluprednate
administered to the eye is about from 32 .mu.g to about 168 .mu.g
(e.g., about 121 .mu.g). In aspects, the implant is sized and
structured to allow for administration in a 27 gauge needle.
[0093] Some embodiments entail administering one ocular implant
having a volume of 653,400,000.+-.10% cubic microns to an eye.
Other embodiments entail administering two ocular implants each
having a volume of 653,400,000.+-.10% cubic microns to an eye. Yet
other embodiments entail administering three ocular implants each
having a volume of 653,400,000.+-.10% cubic microns to an eye. Yet
other embodiments entail administering three or more ocular
implants each having a volume of 653,400,000.+-.10% cubic microns
to an eye. In some embodiments, each of the aforementioned ocular
implants having a volume of 653,400,000.+-.10% cubic microns
contains a difluprednate content of from about 200 .mu.g to about
500 .mu.g. In some aspects, the implants comprise about 390 .mu.g
difluprednate.
[0094] Some embodiments entail administering one ocular implant
having a volume of 540,000,000.+-.10% cubic microns to an eye.
Other embodiments entail administering two ocular implants each
having a volume of 540,000,000.+-.10% cubic microns to an eye. Yet
other embodiments entail administering three ocular implants each
having a volume of 540,000,000.+-.10% cubic microns to an eye. Yet
other embodiments entail administering three or more ocular
implants each having a volume of 540,000,000.+-.10% cubic microns
to an eye. In some embodiments, each of the aforementioned ocular
implants having a volume of 540,000,000.+-.10% cubic microns
contains a difluprednate content of from about 200 .mu.g to about
500 .mu.g. In some aspects, the implants comprise about of from 390
.mu.g to about 480 .mu.g difluprednate. In aspects which entail
administering two ocular implants to an eye, said implants comprise
about of from 390 .mu.g to about 480 .mu.g (e.g., 402.5 .mu.g)
difluprednate per implant, and the amount of difluprednate
administered to the eye is from about 780 .mu.g to about 960 .mu.g
(e.g., 805 .mu.g). In aspects which entail administering three
ocular implants to an eye, said implants comprise from about 90
.mu.g to about 480 .mu.g (e.g., about 402.5 .mu.g) difluprednate
per implant, and the amount of difluprednate administered to the
eye is 1170 .mu.g to about 2880 .mu.g (e.g., about 1207.5 .mu.g).
In aspects, the implant is sized and structured to allow for
administration in a 21 gauge needle or a 22 gauge needle.
[0095] Some embodiments entail administering one ocular implant
having a volume of 35,100,000.+-.10% cubic microns to an eye. Other
embodiments entail administering two ocular implants each having a
volume of 35,100,000.+-.10% cubic microns to an eye. Yet other
embodiments entail administering three ocular implants each having
a volume of 35,100,000.+-.10% cubic microns to an eye. Yet other
embodiments entail administering three or more ocular implants each
having a volume of 35,100,000.+-.10% cubic microns to an eye. In
some embodiments, each of the aforementioned ocular implants having
a volume of 35,100,000.+-.10% cubic microns contains a
difluprednate content of from about 16 .mu.g to about 24 .mu.g. In
some aspects, the implants comprise about 20 .mu.g difluprednate
per implant. In aspects, the implant is sized and structured to
allow for administration in a 24 or 25 gauge needle.
[0096] Some embodiments entail administering one ocular implant
having a volume of 960,000,000.+-.10% cubic microns to an eye.
Other embodiments entail administering two ocular implants each
having a volume of 960,000,000.+-.10% cubic microns to an eye. Yet
other embodiments entail administering three ocular implants each
having a volume of 960,000,000.+-.10% cubic microns to an eye. Yet
other embodiments entail administering three or more ocular
implants each having a volume of 960,000,000.+-.10% cubic microns
to an eye. In some embodiments, each of the aforementioned ocular
implants having a volume of 960,000,000.+-.10% cubic microns
contains a difluprednate content of from 200 .mu.g to 650
.mu.g,
[0097] Some embodiments taught herein provide a biocompatible
ocular implant, comprising: at least one therapeutic agent that is
homogeneously dispersed within a. biocompatible polymer matrix;
wherein said biocompatible ocular implant is formulated to release
a therapeutically effective amount of the at least one therapeutic
agent for a period of time of at least about 2 days upon
administration to a. patient; and wherein said at least one
biocompatible ocular implant demonstrates an in vitro release
profile as set fbrth in the present disclosure. Other embodiments
taught herein provide a biocompatible ocular implant, comprising:
at least one therapeutic agent that is homogeneously dispersed
within a biocompatible polymer matrix; wherein said biocompatible
ocular implant is formulated to release a therapeutically effective
amount of the at least one therapeutic agent for a period of time
up to about 2 days upon administration to a patient, at which point
approximately 100% of the at least one therapeutic agent will have
been released; and wherein said at least one biocompatible ocular
implant demonstrates an in vitro release profile as taught
herein.
[0098] In particular embodiments, the disclosure provides for
biocompatible ocular implants that demonstrate an in vivo release
profile corresponding to the in vitro release profiles depicted by
the implants of the FIGs.
[0099] In particular embodiments, the disclosure provides for
biocompatible ocular implants that demonstrate PK characteristics
corresponding to the PK characteristics depicted by the implants of
the FIGs.
[0100] In particular embodiments, the disclosure provides for
biocompatible rapid release extended treatment ocular implants.
[0101] Further, the disclosure provides for polymer matrix
compositions that demonstrate the release profiles illustrated in
any of the disclosed figures or tables, or release profiles that
are mathematically derivable from the data in said figures and
tables.
[0102] In some aspects, the ocular implant is formulated for
prevention and/or treatment of post-operative inflammation. In some
aspects, the ocular implant is formulated for prevention of
post-operative inflammation. In some aspects, the ocular implant is
formulated for treating post-operative inflammation, allergy
treatment or prevention, pain treatment or prevention, combinations
thereof or the like.
[0103] In one embodiment, the ocular implant is sized and
structured to allow for implantation of the implant into the
subconjunctival region of a human eye.
[0104] In one embodiment, the ocular implant is sized and
structured to allow for implantation of the implant into the
intracameral region of a human eye.
[0105] In some aspects, the ocular implant is formulated to not
increase in size by more than 5% during the entire period between
initial administration to a patient and degradation or dissolution
of the implant.
[0106] In some aspects, the ocular implant is sized and structured
to allow for administration with a 19 to 30 gauge needle. In an
aspect, the implant is sized and structured to allow for
administration with a 21 gauge needle. In an aspect, the implant is
sized and structured to allow for administration with a 22 gauge
needle. In an aspect, the implant is sized and structured to allow
for administration with a 24 gauge needle. In an aspect, the
implant is sized and structured to allow for administration with a
25 gauge needle. In an aspect, the implant is sized and structured
to allow for administration with a 26 gauge needle. In an aspect,
the implant is sized and structured to allow for administration
with a 27 gauge needle. The needle may have walls that are normally
dimensioned, thin walls, or ultrathin walls.
[0107] In an aspect, the implant is sized and structured to allow
for intracameral placement into a human eye via administration with
a 27 gauge needle.
[0108] In an aspect, the implant is sized and structured to allow
for subconjunctival placement into a human eye via administration
with 21 or 22 gauge needles.
[0109] A particular aspect of the present disclosure is that the
present implants can be designed with a size and shape to maximize
needle fit and minimize needle gauge. In particular embodiments,
the inner diameter of the needle is not more than between about
5-50 microns larger than the maximum cross-sectional dimension of
the implant.
[0110] In an embodiment, the inner diameter of the needle is not
more than about 15 micrometers larger than the maximum
cross-sectional dimension of the implant.
[0111] In some embodiments, the implant and needle form a kit,
where the implants are designed to have a maximum cross-sectional
dimension that is not more than about 25, 20, 15, 10, or
micrometers smaller than the inner diameter of the needle.
[0112] In some embodiments, the implants are cylindrical in shape
and the cross-sectional diameter of the cylindrical implant is not
more than about 25, 20, 15, 10, or 5 microns smaller than the inner
diameter of the needle.
[0113] In a particular embodiment, the ocular implant is
manufactured by a process comprising: 1) providing a mold, wherein
the mold comprises a plurality of recessed areas formed therein; 2)
disposing a volume of liquid material in the plurality of recessed
areas; 3) forming a plurality of substantially uniform implants;
and 4) harvesting the implants from the patterned template, wherein
each of said implants substantially mimics the recessed areas.
[0114] Some embodiments comprise a kit for administering a
biocompatible ocular implant, comprising: (a) at least one
biocompatible ocular implant; wherein said at least one
biocompatible ocular implant comprises at least one therapeutic
agent that is homogeneously dispersed within a biocompatible
polymer matrix; and (b) a single use ocular implant applicator that
comprises a needle or needlelike device. In some embodiments, the
needle or needlelike device is 27 gauge or larger. In some aspects,
the needle or needlelike device is 21 or 22 gauge. In some aspects,
the needle or needlelike device is 25 or 26 gauge.
[0115] In some aspects, the implants produced according to the
present disclosure exhibit a therapeutic agent release profile that
has very low inter-implant variability. The therapeutic agent
release profiles exhibited by some implants of the present
disclosure are consistent across implants and demonstrate variation
that is not statistically significant. Consequently, the drug
release profiles demonstrated by embodiments of the implants
exhibit coefficients of variation that are within a confidence
interval and not biologically relevant.
[0116] In some aspects, the therapeutic agent content amongst
implants of a given configuration is highly consistent. In
particular embodiments, the implants of the present disclosure
possess a therapeutic agent content that does not vary
significantly amongst implants of a specific configuration. In an
embodiment, the therapeutic agent content of implants having a
given configuration does not vary in a statistically significant
manner from one another.
BRIEF DESCRIPTION OF THE DRAWINGS
[0117] FIG. 1A and FIG. 1B show release profiles for a series of
implants tested under in vitro conditions. FIG. 1A shows the
percent difluprednate released as a function of time (days). FIG.
1B shows the release rate (.mu.g/day) as a function of time
(days).
[0118] FIG. 2A to 2F show release profiles for a series of implants
tested under in vitro conditions. FIG. 2A shows the percent
difluprednate released as a function of time (days). FIG. 2B shows
the percent difluprednate released as a function of time (days).
FIG. 2C shows the release rate (.mu.g/day) as a function of time
(days). FIG. 2D shows the release rate (.mu.g/day) as a function of
time (days). FIG. 2E shows the cumulative difluprednate released
(.mu.g) as a function of time (days). FIG. 2F shows the cumulative
difluprednate released (.mu.g) as a function of time (days)
[0119] FIG. 3 shows the Hackett-McDonald Ocular Exam Score as a
function of time (days) to an in vivo animal study.
[0120] FIG. 4 shows the difluprednate (.mu.g) present in retrieved
implants as a function of time (days).
[0121] FIG. 5A to 5C shows release profiles for a series of
implants tested under in vitro conditions. FIG. 5A shows the
percent difluprednate released as a function of time (days). FIG.
5B shows the release rate (.mu.g/day) as a function of time (days).
FIG. 5C shows the cumulative difluprednate released (.mu.g) as a
function of time (days).
[0122] FIG. 6A to 6C show release profiles for a series of implants
tested under in vitro conditions. FIG. 6A shows the percent
difluprednate released as a function of time (days). FIG. 6B shows
the release rate (.mu.g/day) as a function of time (days). FIG. 6C
shows the cumulative difluprednate released (.mu.g) as a function
of time (days).
[0123] FIG. 7 shows the Hackett-McDonald Ocular Exam Score as a
function of time (days) for an in vivo animal study.
[0124] FIG. 8 shows the Hackett-McDonald Ocular Exam Score as a
function of time (days) for an in vivo animal study.
[0125] FIG. 9 illustrates the effect of subconjunctival ENV905 in a
corneal incision/paracentesis rabbit model of post-operative
inflammation.
[0126] FIG. 10 illustrates the effect of subconjunctival ENV905 in
a corneal incision/paracentesis rabbit model of post-operative
inflammation.
[0127] FIG. 11 illustrates the effect of subconjunctival ENV905 in
a phacoemulsification/paracentesis rabbit model of post-operative
inflammation.
[0128] FIG. 12 illustrates the effect of intracameral ENV905 in a
corneal incision/paracentesis rabbit model of post-operative
inflammation.
[0129] FIG. 13 illustrates the effect of intracameral delivery in a
phacoemulsification/paracentesis rabbit model of post-operative
inflammation.
[0130] FIG. 14 illustrates the Total Hackett-McDonald Ophthalmic
Exam Score (Mean.+-.SD) for all intracameral implants tested in an
in vivo study.
[0131] FIG. 15 illustrates the Total Hackett-McDonald Ophthalmic
Exam Score (Mean.+-.SD) for all intracatneral and subconjunctival
implants tested in an in vivo study.
[0132] FIG. 16 illustrates the Total Hackett-McDonald Ophthalmic
Exam Scores from a non-GLP tolerability study.
[0133] FIG. 17 illustrates plasma Desacetyl Difluprednate (DFB)
levels in rabbits after IC administration of ENV905-1 and SCJ
administration of ENV905-2.
[0134] FIG. 18 illustrates Difluprednate (DFBA) and Desacetyl
Difluprednate (DFB) levels in various ocular matrixes collected in
rabbits after IC administration of ENV905-1, including: aqueous
humor, bulbar conjunctiva, cornea (enriched with trabecular
meshwork), iris/ciliary body, and retina.
[0135] FIG. 19 illustrates Difluprednate (DFBA) and Deascetyl
Difluprednate (DFB) levels in various ocular matrixes collected in
rabbits after SCJ administration of ENV905-2, including: aqueous
humor, bulbar conjunctiva, subconjunctival dose site; cornea
(enriched with trabecular meshwork), iris/ciliary body, and
retina.
[0136] FIG. 20 illustrates the Total Hackett-McDonald Ophthalmic
Exam Score (Mean.+-.SEM) for the compositions tested in the
ENV905-PRE-008 study over 30 days. DUREZOL.RTM. (0.05%), ENV905-1
(placebo), ENV905-1 (difluprednate), ENV905-3 (difluprednate), and
ENV905-4 (difluprednate) were evaluated in this study.
[0137] FIG. 21 illustrates Deascetyl Difluprednate (DFB) levels in
blood plasma (ng/mL) for the compositions tested in the
ENV905-ADME-002 study over 28 days. DUREZOL.RTM. (0.05%), ENV905-1
(1.times. implant), ENV905-1 (2.times. implant), and ENV905-1
(3.times. implant) were evaluated in this study.
[0138] FIG. 22A illustrates Difluprednate levels in the cornea
(ng/mL) for the compositions tested in the ENV905-ADME-002 study
over 28 days. DUREZOL.RTM. (0.05%), ENV905-1 (1.times. implant),
ENV905-1 (2.times. implant), and ENV905-1. (3.times. implant) were
evaluated in this study.
[0139] FIG. 22B illustrates Desacetyl Difluprednate (DFB) levels in
the cornea (ng/mL) for the compositions tested in the
ENV905-ADME-002 study over 28 days. DUREZOL.RTM. (0.05%), ENV905-1
(1.times. implant), ENV905-1 (2.times. implant), and ENV905-1.
(3.times. implant) were evaluated in this study.
[0140] FIG. 23A. illustrates Difluprednate (DFB) levels in the
trabecular meshwork (ng/mL) for the compositions tested in the
ENV905-ADME-002 study over 28 days. DUREZOL.RTM. (0.05%), ENV905-1
(1.times. implant), EN V905-1 (2.times. implant), and EN V905-1
(3.times. implant) were evaluated in this study.
[0141] FIG. 23B. illustrates Desacetyl Difluprednate (DFB) levels
in the trabecular meshwork (ng/mL) for the compositions tested in
the ENV905-ADME-002 study over 28 days. DUREZOL.RTM. (0.05%),
ENV905-1 (1.times. implant), ENV905-1 (2.times. implant), and
ENV905-1 (3.times. implant) were evaluated in this study.
[0142] FIG. 24A. illustrates Desacetyl Difluprednate (DFB) levels
in the iris/ciliary body (ng/mL) for the compositions tested in the
ENV905-ADME-002 study over 28 days. DUREZOL.RTM. (0.05%), ENV905-1
(1.times. implant), ENV905-1 (2.times. implant), and ENV905-1
(3.times. implant) were evaluated in this study.
[0143] FIG. 24B. illustrates Desacetyl Difluprednate (DFB) levels
in the iris/ciliary body (ng/mL) for the compositions tested in the
ENV905-ADME-002 study over 28 days. DUREZOL.RTM. (0.05%), ENV905-1
(1.times. implant), ENV905-1 (2.times. implant), and ENV9OS-1
(3.times. implant) were evaluated in this study.
[0144] FIG. 25A illustrates the central corneal thickness data (%
change from baseline) in rabbits from a non-GLP tolerability study
measured after injection, and after administration of ENV905-1
(placebo), ENV905-1 (difluprednate), ENV905-5 (placebo), and
ENV905-5 (difluprednate).
[0145] FIG. 25B illustrates the inferior corneal thickness data (%
change from baseline) in rabbits from a non-GLP tolerability study
measured after injection, and after administration of ENV905-1
(placebo), ENV905-5 (placebo), and EN V905-5 (difluprednate),
[0146] FIG. 26 illustrates systemic exposure to Deascetyl
Difluprednate (DFB) for ENV905-1 (44.0 .mu.g/eye) compared to
DUREZOL.RTM..
[0147] FIG. 27 illustrates exposure to Deascetyl Difluprednate
(DFB) in the Iris/Ciliary Body for ENV905-1 (44.0 .mu.g/eye)
compared to DUREZOL.RTM..
[0148] FIG. 28 illustrates exposure to Desacetyl Difluprednate
(DFB) in the Trabecular Meshwork for EN V905-1 (44.0 .mu.g/eye)
compared to DUREZOL.RTM..
[0149] FIG. 29 illustrates intraocular pressure measured overtime
for ENV905-1 (without difluprednate), ENV905-1 (low; 1 implant per
eye), ENV905-1 (mid; 2 implants per eye), and ENV905-1 (3 implants
per eye).
[0150] FIG. 30 Deascetyl Difluprednate (DFB) pressure measured
overtime for ENV905-1 (without difluprednate), ENV905-1 (1 implant
per eye), ENV905-1 (2 implants per eye), and ENV905-1 (3 implants
per eye).
[0151] FIG. 31A illustrates Difluprednate (DFB) levels in bulbar
conjunctiva (ng/mL) for the compositions tested in the
ENV905-ADME-002 study over 28 days. DUREZOL.RTM. (0.05%), ENV905-1
(1.times. implant), ENV905-1 (2.times. implant), and EN V905-1
(3.times. implant) were evaluated in this study.
[0152] FIG. 31B illustrates Desacetyl Difluprednate (DFB) levels in
bulbar conjunctiva (ng/mL) for the compositions tested in the
ENV905-ADMF-002 study over 28 days. DUREZOL.RTM. (0.05%), ENV905-1
(1.times. implant), ENV905-1 (2.times. implant), and ENV905-1
(3.times. implant) were evaluated in this study.
[0153] FIG. 32A illustrates Difluprednate levels in retina (ng/mL)
for the compositions tested in the ENV905-ADMF-002 study over 28
days. DUREZOL.RTM. (0.05%), ENV905-1 (1.times. implant), ENV905-1
(2.times. implant), and ENV905-1 (3.times. implant) were evaluated
in this study.
[0154] FIG. 32B illustrates Desacetyl Difluprednate (DFB) levels in
retina (ng/mL) for the compositions tested in the ENV905-ADME-002
study over 28 days. DUREZOL.RTM. (0.05%), ENV905-1 (1.times.
implant), ENV905-1 (2.times. implant), and ENV905-1 (3.times.
implant) were evaluated in this study.
[0155] FIG. 33A illustrates Difluprednate levels in aqueous humor
(ng/mL) for the compositions tested in the EISV905-ADME-002 study
over 28 days. DUREZOL.RTM. (005%), ENV905-1 implant), ENV905-1
(2.times. implant), and ENV905-1 (3.times. implant) were evaluated
in this study.
[0156] FIG. 33B illustrates Desacetyl Difluprednate (DFB) levels in
aqueous humor (ng/mL) for the compositions tested in the
ENV905-ADME-002 study over 28 days. DUREZOL.RTM. (0.05%), ENV905-1
(1.times. implant), ENV905-1 (2.times. implant), and ENV905-1
(3.times. implant) were evaluated in this study.
[0157] FIG. 34 illustrates the central corneal thickness data
(.mu.m) in rabbits from a toxicity study measured after
administration of ENV905-1 (placebo) and ENV905-1 (active).
DETAILED DESCRIPTION
[0158] Provided herein are pharmaceutical compositions for treating
or preventing an ocular condition. In embodiments, the
pharmaceutical composition comprises: a biocompatible polymer
matrix and a therapeutic agent, which is included in the polymer
matrix. The therapeutic agent may be dispersed homogeneously
throughout the polymer matrix.
[0159] As described herein, multiple pharmaceutical compositions
have been fabricated and/or contemplated in the form of an implant,
resulting in highly effective pharmaceutically active products,
including ocular therapeutic treatments, including: (1) sustained
release ocular implants, as well as (2) immediate/rapid delivery
and extended treatment ocular implants.
[0160] In various embodiments, these pharmaceutical compositions
include a therapeutic agent dispersed throughout a polymer matrix
formed into an ocular implant. In some aspects, the ocular implant
degrades slowly in a human eye and gradually, or in a sustained
way, releases the active therapeutic agent. In other aspects, the
ocular implant dissolves immediately upon being exposed to the
physiological conditions of an eye, and the active therapeutic
agent is available to treat the loci for an extended amount of
time.
[0161] In a particular embodiment, the pharmaceutical composition
of the present disclosure comprises: i) a biocompatible polymer or
polymers, and ii) a therapeutic agent such as, for example, a drug
effective for use in the prevention and/or treatment of an ocular
condition, such as post-operative inflammation and/or pain.
[0162] Definitions
[0163] "About" means plus or minus a percent (e.g., .+-.10% or
.+-.5%) of the number, parameter, or characteristic so qualified,
which would be understood as appropriate by a skilled artisan to
the scientific context in which the term is utilized. Furthermore,
since all numbers, values, and expressions referring to quantities
used herein, are subject to the various uncertainties of
measurement encountered in the art, then unless otherwise
indicated, all presented values may be understood as modified by
the term "about."
[0164] As used herein, the articles "a," "an," and "the" may
include plural referents unless otherwise expressly limited to
one-referent, or if it would be obvious to a skilled artisan from
the context of the sentence that the article referred to a singular
referent.
[0165] Where a numerical range is disclosed herein, then such a
range is continuous, inclusive of both the minimum and maximum
values of the range, as well as every value between such minimum
and maximum values. Still further, where a range refers to
integers, every integer between the minimum and maximum values of
such range is included. In addition, where multiple ranges are
provided to describe a feature or characteristic, such ranges can
be combined. That is to say that, unless otherwise indicated, all
ranges disclosed herein are to be understood to encompass any and
all subranges subsumed therein. For example, a stated range of from
"1 to 10" should be considered to include any and all subranges
between the minimum value of 1 and the maximum value of 10.
Exemplary subranges of the range "1 to 10" include, but are not
limited to, 1 to 6.1, 3.5 to 7.8, and 5.5 to 10.
[0166] As used herein, the term "polymer" is meant to encompass
both homopolymers (polymers having only one type of repeating unit)
and copolymers (a polymer having more than one type of repeating
unit).
[0167] "Biodegradable polymer" means a polymer or polymers, which
degrade in vivo, under physiological conditions. The release of the
therapeutic agent occurs concurrent with, or subsequent to, the
degradation of a biodegradable polymer over time.
[0168] The terms "biodegradable" and "bioerodible" are used
interchangeably herein. A biodegradable polymer may be a
homopolymer, a copolymer, or a polymer comprising more than two
different polymeric units.
[0169] As used herein, the term "biocompatible" means a material,
such as a polymer, that is compatible with living tissue.
Biocompatible polymers may be biodegradable, bioerodible, or
dissolvable.
[0170] As used herein, the term "polymer matrix" refers to a
homogeneous mixture of polymers. In other words, the polymer matrix
does not include a mixture of polymers wherein one portion of the
polymer matrix is different from the other portion by ingredient,
density, and etc. For example, the polymer matrix does not include
a composition containing a core and one or more outer layers, nor a
composition containing a drug reservoir and one or more portions
surrounding the drug reservoir. The mixture of polymers may be of
the same type, e.g. two different PEG polymers, or of different
types, e.g. PEG polymers combined with PCL polymers.
[0171] "Ocular condition" means a disease, ailment, or condition,
which affects or involves the ocular region.
[0172] The term "hot-melt extrusion" or "hot-melt extruded" is used
herein to describe a process, whereby a blended composition is
heated and/or compressed to a molten (or softened) state and
subsequently forced through an orifice, where the extruded product
(extrudate) is formed into its final shape, in which it solidifies
upon cooling.
[0173] The term "non-extruded implant" or "non-hot melt extruded
implant" refers to an implant that was not manufactured in a
process that utilizes an extrusion step.
[0174] As used herein, "drug release" refers to the release of the
at least one therapeutic agent, or drug, from an implant. The drug
release may be sustained release, controlled release, or rapid
release.
[0175] "Sustained release" or "controlled release" refers to the
release of at least one therapeutic agent, or drug, from an implant
at a predetermined rate. Sustained release implies that the
therapeutic agent is not released from the implant sporadically, in
an unpredictable fashion. The term "sustained release" may include
a "burst phenomenon" associated with deployment. In some example
embodiments, an initial burst of at least one therapeutic agent may
be desirable, followed by a more gradual release thereafter. The
release rate may be steady state (commonly referred to as "timed
release" or zero order kinetics), that is the at least one
therapeutic agent is released in even amounts over a predetermined
time (with or without an initial burst phase), or may be a gradient
release.
[0176] In some embodiments, the ocular implant polymer matrix fully
disintegrates, dissolves, dissociates, &solutes, and/or
otherwise completely diminishes, upon placement into the eye under
normal physiological conditions. In these embodiments, the ocular
implant is often termed a "rapid delivery vehicle" or "rapid
release vehicle." The ocular implant fully, or nearly completely,
dissolves upon placement into the eye and consequently releases the
entirety of the therapeutic agent payload dispersed within said
ocular implant polymer matrix. Consequently, in these embodiments,
it is the pharmacokinetics associated with the therapeutic agent
contained within the ocular implant that allows for the achievement
of an extended treatment concentration of drug, in the surrounding
tissues of the eye that prevents and/or treats a condition of the
eye, such as for example: post-operative inflammation, allergy,
pain, combinations thereof, and the like. For example, factors such
as the therapeutic agent content, the water solubility of the
therapeutic agent, the route of administration, and the
physicochemical properties of the therapeutic agent all factor to
control the "extended treatment" availability of the therapeutic
agent to the loci of the eye. In some aspects, the physiochemical
attributes of difluprednate, in combination with the rapid delivery
ocular implant (e.g. a PEG based implant that immediately dissolves
upon placement into an aqueous environment) and its subsequent
subconjunctival or intracameral placement, leads to an extended
treatment bioavailability of difluprednate for at least 2 days, or
7 days, or 14 days, or 20 days, or at least about 28 days in an
eye.
[0177] "Therapeutically effective amount" means a level or amount
of a therapeutic agent needed to treat an ocular condition; or the
level or amount of a therapeutic agent that produces a therapeutic
response or desired effect in the subject to which the therapeutic
agent was administered. Thus, a therapeutically effective amount of
a therapeutic agent, such as a difluprednate, is an amount that is
effective in reducing at least one symptom of an ocular condition.
Achieving a therapeutically effective amount may be achieved
through sustained release of a therapeutic agent from an implant or
through extended treatment when a therapeutic agent is rapidly
released from an implant and the therapeutic agent provides
extended treatment over time.
[0178] As used herein, the term "baseline" refers to a proper
reference measurement established prior to surgery. The baseline
measurement can be obtained by any suitable method. In some
embodiments, "baseline" refers to the thickness of the cornea prior
to surgery. In other embodiments, "baseline" refers to the
thickness of the cornea prior to administration of an ocular
implant. In still other embodiments, "baseline" refers intraocular
pressure measured prior to surgery. In yet other embodiments,
"baseline" refers to the intraocular pressure of a healthy eye.
[0179] As used herein, PEG is used to represent poly(ethylene
glycol) of all molecular weights including polyethylene oxides.
[0180] Ocular Anatomy
[0181] In particular embodiments, the implants described herein are
subconjunctival implants manufactured for placement into the
subconjunctival region of the human eye.
[0182] In particular embodiments, the implants described herein are
intracameral implants manufactured for placement into the
intracameral region of the human eye.
[0183] In certain embodiments, the steady and sustained release of
therapeutic agent from the implant achieves a concentration of drug
in the surrounding tissues of the eye that prevents and/or treats a
condition of the eye, such as for example post-operative
inflammation, allergy, pain, combinations thereof, and the
like.
[0184] Therapeutic agents for the treatment of ocular inflammation
are typically administered to the eye in solution-based
formulations. For example, DUREZOL.RTM. is an emulsion whiCh is
applied topically to the eye as eye drops, and U.S. Patent
Application Publication 2016/0120879 describes injectable
suspensions which are administered into the anterior chamber of the
eye. However, such solution-based formulations suffer from
imprecise localization of the active at the site of inflammation,
which reduces efficacy. Additionally, injectable suspensions can
result in adverse events, such as blurred vision, due to
localization of the suspension near the cornea. Further, the
therapeutic agents contained within the suspension can polymerize
after administration, which also reduces efficacy.
[0185] In contrast to solution-based formulations, the implants
disclosed herein are formulated to remain localized at the site of
administration, which improves efficacy and reduces the incidence
of adverse events associated with translocation of injectable
suspensions. The implants disclosed herein are formulated to
prevent aggregation of the therapeutic agents. Further, the
implants exhibit improved dose uniformity compared to
solution-based formulations.
[0186] Biocompatible Polymers
[0187] In certain embodiments, the implants described herein are
engineered to provide maximal approximation of the implant to the
human eye. In certain embodiments, the implants are made of
polymeric materials.
[0188] In embodiments, the polymer materials used to form the
implants described herein are biodegradable. In embodiments, the
polymer materials may be any combination of polylactic acid,
glycolic acid, polycaprolactone (PCL), and co-polymers thereof,
which provides sustained-release of the therapeutic agent into the
eye over time.
[0189] Suitable polymeric materials or compositions for use in the
implants include those materials which are compatible, which is
biocompatible, with the eye so as to cause no substantial
interference with the functioning or physiology of the eye. Such
polymeric materials may be biocompatible, biodegradable, or
bioerodible In particular embodiments, examples of useful polymeric
materials include, without limitation, such materials derived from
and/or including organic esters and organic ethers, which when
degraded result in physiologically acceptable degradation products.
Also, polymeric materials derived from and/or including,
anhydrides, amides, orthoesters and the like, by themselves or in
combination with other monomers, may also find use in the present
disclosure. The polymeric materials may be addition or condensation
polymers. The polymeric materials may be cross-linked or
non-cross-linked. For some embodiments, besides carbon and
hydrogen, the polymers will include at least one of oxygen and
nitrogen. The oxygen may be present as oxy, e.g. hydroxy or ether,
carbonyl, e.g. non-oxo-carbonyl, such as carboxylic acid ester, and
the like. The nitrogen may be present as amide, cyano and
amino.
[0190] In embodiments, the implant polymer matrix is selected from:
(1) PEG with no other polymers mixed in (disclosed in further
detail herein) to form a rapid release delivery vehicle, meaning,
less than about, 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour for
the implant to dissolve and release its active cargo; (2) PEG/PLGA
mixed polymer matrix particles (disclosed in further detail herein)
that give a longer release and degradation profile for the
implants, which extend for up to 1 day, 2 days, 5 days, 10 days,
and 14 days; and (3) PEG/PCL mixed polymer matrix particles
(disclosed in further detail herein), which extend release for more
than 14 days, 20 days, or 28 days.
[0191] In one embodiment, polymers of hydroxyaliphatic carboxylic
acids, either homopolymers or copolymers, and polysaccharides are
useful in the implants. Polyesters can include polymers of D-lactic
acid, L-lactic acid, racemic lactic acid, glycolic acid,
polycaprolactone, co-polymers thereof, and combinations
thereof.
[0192] Some characteristics of the polymers or polymeric materials
for use in embodiments of the present disclosure may include
biocompatibility, compatibility with the selected therapeutic
agent, ease of use of the polymer in making the therapeutic agent
delivery systems described herein, a desired half-life in the
physiological environment, and hydrophilicity.
[0193] In one embodiment, the biocompatible polymer matrix used to
manufacture the implant is a polyether, for example a polyethylene
glycol (PEG). PEGS are prepared by polymerization of ethylene oxide
and are available in a wide range of molecular weights. PEG has
found medical use as an excipient in pharmaceutical products, in
lubricating eye drops, film coatings, and ointment bases. PEG may
be synthesized at a variety of molecular weights. Used herein are
PEGs with molecular weights that include 500-100,000,000 Da, 2,000
Da, 3,000 Da, 3,300 Da, 3,350 Da, 100,000 Da, 3,000 Da, 35,000 Da,
100,000 Da, and 1,000,000 Da. In some aspects, PEGs with molecular
weights from 500 to 1,000,000 Daltons are used. PEG is represented
by the general structure (1).
##STR00001##
[0194] In one embodiment utilizing PEGs, the ocular implant
formulations will be comprised of micronized difluprednate, the
active ingredient, and a blend of two PEGs with different average
molecular weights, the inactive ingredients. The PEGs will have an
average molecular weight of 100,000 daltons (Da) (PEG 100K) and
3,350 Da (PEG 3,350). These water-soluble PEGS function as both a
diluent and a binder for the micronized difluprednate to form an
injectable, solid implant formulation.
[0195] PEG 100K is a relatively large and hard polymer. Because of
these physical characteristics, implants comprising PEG 100K as the
sole polymer in a polymer matrix typically do not contain a
homogenous dispersion of a therapeutic agent, and the amount of
therapeutic agent between batches is not uniform. PEG 3,350 is a
relatively small and soft polymer. PEG 3,350 is difficult to handle
during processing, which typically results in non-uniform dosages
of therapeutic agent between batches. However, the inventors
discovered that the combination of PEG 100K and PEG 3,350, at the
ratios disclosed herein, can in some aspects be critical to
fabricating implants with dose uniformity. p In embodiments, the
PEGs are long-chain polymers of ethylene oxide with a formula of
OH--(CH.sub.2--CH.sub.2--O).sub.n--H, where n is the average number
of oxyethylene groups present in the molecule. These polymers have
been used extensively in approved products across multiple routes
of administration including oral, topical, ophthalmic, rectal,
vaginal, intrasynovial, intra-articular, intramuscular, and
intravenous (Inactive Ingredients Database). PEGs are generally
considered to have low toxicity by all routes of administration,
and have been shown to be very safe in a large battery of tests
using a large range of routes and molecular weights (Herold 1982,
Smyth 1947, Smyth 1950, Smyth 1970, Webster 2009).
[0196] In one embodiment, the biocompatible polymer matrix used to
manufacture the implant is a synthetic aliphatic polyester, for
example a polycaprolactone. PCL is formed by ring opening
polymerization of .epsilon.-caprolactone. Polycaprolactone degrades
by hydrolysis of its ester linkages. Polycaprolactone has found use
in medical devices such as sutures, tissue scaffold, or as dental
splints. Polycaprolactone may be synthesized at a variety of
molecular weights. Preferred molecular weights, in some aspects,
include 2,000 Da, 14,000 Da, and 45,000 Da. In some aspects, PCL
with a molecular weight of from 2000 to 45,000 Daltons are used.
Polycaprolactone is represented by the general structure (2).
##STR00002##
[0197] In one embodiment, the biocompatible polymer matrix used to
manufacture the implant is a synthetic aliphatic polyester, for
example, a polymer of lactic acid and/or glycolic acid, and
includes poly-(D,L-lactide) (PLA), polyglycolic acid (PGA), and/or
the copolymer poly-(D, L-lactide-co-glycolide) (PLGA).
[0198] PLGA and PLA polymers are known to degrade via backbone
hydrolysis (bulk erosion) and the final degradation products are
lactic and glycolic acids, which are non-toxic and considered
natural metabolic compounds. Lactic and glycolic acids are
eliminated safely via the Krebs cycle by conversion to carbon
dioxide and water.
[0199] PLGA is synthesized through random ring-opening
co-polymerization of the cyclic dimers of glycolic acid and lactic
acid. Successive monomeric units of glycolic or lactic acid are
linked together by ester linkages. The ratio of lactide to
glycolide can be varied, altering the biodegradation
characteristics of the product. By altering the ratio it is
possible to tailor the polymer degradation time. Importantly, drug
release characteristics are affected by the rate of biodegradation,
molecular weight, and degree of crystallinity in drug delivery
systems. By altering and customizing the biocompatible polymer
matrix, the drug delivery profile can be changed.
[0200] PCL, PLA, PGA, and PLGA are cleaved predominantly by
non-enzymatic hydrolysis of its ester linkages throughout the
polymer matrix, in the presence of water in the surrounding
tissues. PCL, PLA, PGA, and PLGA polymers are biocompatible,
because they undergo hydrolysis in the body to produce the original
monomers. Lactic and glycolic acids are nontoxic and eliminated
safely via the Krebs cycle by conversion to carbon dioxide and
water. The biocompatibility of PCL, PLA, PGA and PLGA polymers has
been further examined in both non-ocular and ocular tissues of
animals and humans. The findings indicate that the polymers are
well tolerated.
[0201] Examples of PLA polymers, which may be utilized in an
embodiment of the disclosure, include the RESOMER.RTM. Product line
available from Evonik Industries identified as, but are not limited
to, R 207 S, R 202 S, R 202 H, R 203 S, R 203 H, R 205 S, R 208, R
206, and R 104 Examples of suitable PLA polymers include both acid
and ester terminated polymers with inherent viscosities ranging
from approximately 0.15 to approximately 2.2 dL/g when measured at
0.1% w/v in CHCl.sub.3 at 25.degree. C. with an Ubbelhode size 0c
glass capillary viscometer.
[0202] The synthesis of various molecular weights of PLA is
possible. In one embodiment, PLA, such as RESUMER.RTM. R208S, with
an inherent viscosity of approximately 1.8 to approximately 2.2
dl/g, can be used. In another embodiment. PLA, such as RESOMER.RTM.
R203S, with an inherent viscosity of approximately 0.25 to
approximately 0.35 dl/g can be used
[0203] Resomer's R203S and R208S are poly(D,L-lactide) or PLA
ester-terminated polymers with the general structure (3):
##STR00003##
[0204] Examples of PLGA polymers, which may be utilized in an
embodiment of the disclosure, include the RESOMER.RTM. Product line
from Evonik Industries, including RG 502. RG 502 H, RG 503, RG 503
H, RG 504, RG 504 H. RG 505, RG 506, RG 653 H, RG 752 H, RG 752 S,
RG 753 H, RG 753 S, RG 755, RG 755 S, RG 756, RG 756 S, RG 757 S,
RG 750 S, RG 858, and RG 858 S. Such PLGA polymers include both
acid and ester terminated polymers with inherent viscosities
ranging from approximately 0.14 to approximately 1.7 dl/g when
measured at 0.1% w/v in CHCl.sub.3 at 25.degree. C. with an
Ubbelhode size 0c glass capillary viscometer. Example polymers used
in various embodiments of the disclosure may include variation in
the mole ratio of D,L-lactide to glycolide from approximately 50:50
to approximately 85:15, including, but not limited to, 50:50,
65:35, 75:25, and 85:15.
[0205] The synthesis of various molecular weights of PLGA with
various D,L-lactide-glycolide ratios is possible. In one
embodiment, PLGA, such as RESOMER.RTM. RG 752 S, with an inherent
viscosity of approximately 0.16 to approximately 0.24 dl/g can be
used as the matrix material of the present implants.
[0206] Resomer RG752S is a poly(D,L-lactide-co-glycolide) or
ester-terminated PLGA copolymer (lactide:glycolide ratio of 75:25)
with the general structure (4):
##STR00004##
[0207] The polymers used to form the implants of the disclosure
have independent properties associated with them that when combined
provide the properties needed to provide release of a
therapeutically effective amount.
[0208] A few of the primary polymer characteristics that control
therapeutic agent release rates are: polymer solubility, the
molecular weight distribution, polymer end group, for example, acid
or ester, and the ratio of polymers and/or copolymers in the
polymer matrix. The present disclosure provides examples of polymer
matrices that possess desirable therapeutic agent release
characteristics by manipulating one or more of the aforementioned
properties to develop a suitable ocular implant.
[0209] Drug Release Profile Manipulation
[0210] The rate of drug release from biocompatible implants depends
on several factors. For example, the surface area of the implant,
the therapeutic agent content, the water solubility of the
therapeutic agent, and the speed of polymer degradation or
dissolution.
[0211] The versatility of PCL, PEG, PGA, PLA, and PLGA allows for
construction of delivery systems to tailor the drug release for
treating a variety of front and back of the eye diseases.
[0212] When the versatility of PCL, PEG, PGA, PLA, and PLGA
polymers are combined with the manufacturing techniques of the
present disclosure, for example PRINT.RTM. (Envisia Therapeutics
Inc.) particle fabrication technology, then a host of custom
tailored and highly consistent and predictable drug release
profiles can be created, which were not possible based upon the
technology of the prior art, such as for example extrusion.
[0213] That is, with the present mold based particle fabrication
technology, implants can be manufactured that exhibit a drug
release profile that has highly reproducible characteristics
implant to implant. The drug release profiles exhibited by various
implants of the present disclosure are consistent implant to
implant and demonstrate variation that is not statistically
significant. Consequently, the drug release profiles demonstrated
by embodiments of the implants exhibit coefficients of variation
that are within a confidence interval and not biologically
relevant. The ability to produce implants that demonstrate such a
high degree of consistent drug release is advancement over the
state of the art.
[0214] Drug Release Kinetics
[0215] Drug release is influenced by many factors including:
polymer composition, therapeutic agent content, implant morphology,
porosity, tortuosity, surface area, method of manufacture, and
deviation from sink conditions, just to name a few. The present
mold based manufacturing techniques utilized in embodiments of the
disclosure are able to manipulate implant morphology, porosity,
tortuosity, and surface area in ways that the prior art methods
were incapable of doing. For instance, the highly consistent drug
release profiles, highly consistent implant morphologies, and
highly consistent homogeneous drug dispersions achievable by the
present methods, were not available to prior art practitioners
relegated to utilizing a heat extrusion based method of
manufacture.
[0216] In general, therapeutic agent release occurs in 3 phases:
(a) an initial burst release of therapeutic agent from the surface,
(b) followed by a period of diffusional release, which is governed
by the inherent dissolution of therapeutic agent (diffusion through
internal pores into the surrounding media) and lastly, (c)
therapeutic agent release associated with biodegradation of the
polymer matrix. The rapid achievement of high therapeutic agent
concentrations, followed by a longer period of continuous
lower-dose release, makes such delivery systems ideally suited for
acute-onset diseases that require a loading dose of therapeutic
agent followed by tapering doses.
[0217] More recent advancements in drug delivery systems have
allowed for biphasic release characteristics with an initial high
(burst) rate of therapeutic agent release followed by sustained
zero-order (linear) kinetic release (i.e., therapeutic agent
release rate from the polymer matrix is steady and independent of
the therapeutic agent concentration in the surrounding milieu) over
longer periods. In addition, when desired for treating chronic
diseases such as elevated IOP, these therapeutic agent delivery
systems can be designed to have steady state release following zero
order kinetics from the onset.
[0218] In aspects, the mono-polymeric PEG implants of the present
disclosure, however, do not follow the above bi and tri phase
release profiles. The PEG implants of the present disclosure, in
embodiments, are rapid release, where the PEG monomers disassociate
with each other when exposed to biologic conditions and the
therapeutic agent captured therein is released into the surrounding
tissues.
[0219] Therapeutic Agents
[0220] Suitable therapeutic agents for use in various embodiments
of the disclosure may be found in the Orange Book published by the
Food and Drug Administration, which lists therapeutic agents
approved for treating post-operative inflammation.
[0221] In some embodiments, the therapeutic agents that can be used
according to the disclosure include: steroids, corticosteroids,
NSAIDs, allergy medications, antihistamines, antibiotics,
pharmaceutically acceptable salts thereof, biologic molecules, and
combinations thereof.
[0222] Suitable examples of the aforementioned steroids include,
but are not limited to, 21-acetoxypregnenolone, alclometasone,
algestone, amcinonide, beclomethasone, betamethasone, budesonide,
chloroprednisone, clobetasol, clobetasone, clocortolone,
cloprednol, corticosterone, cortisone, cortivazol, deflazacort,
desonide, desoximetasone, dexamethasone, diflorasone,
diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide,
flumethasone, fluocinolone acetonide, fluocinonide, fluocortin
butyl, fluocortolone, fluorometholone, fluperolone acetate,
fluprednidene acetate, fluprednisolone, flurandrenolide,
fluticasone propionate, formocortal, halcinonide, halobetasol
propionate, halometasone, halopredone acetate, hydrocortamate,
hydrocortisone, loteprednol etabonate, mazipredone, medrysone,
meprednisone, methylprednisolone, mometasone furoate,
paramethasone, prednicarbate, prednisolone, prednisolone
25-diethylamine-acetate, prednisolone sodium phosphate, prednisone,
prednival, prednylidene, rimexolone, tixocortol, triamcinolone,
triamcinolone acetonide, triamcinolone benetonide, triamcinolone
hexacetonide, fluocinolone.
[0223] Suitable examples of the aforementioned corticosteroids
include, but are not limited to, cortisone, prednisolone,
fluorometholone, dexamethasone, difluprednate, medrysone,
loteprednol, fluazacort, hydrocortisone, prednisone, betamethasone,
prednisone, prednisolone, fluocinolone acetonide,
methylprednisolone, triamcinolone hexacetonide, paramethasone
acetate, diflorasone, fluocinonide, rimexolone, derivatives
thereof, and mixtures thereof.
[0224] Suitable examples of the aforementioned NSAIDs include, but
are not limited to, aspirin, diclofenac, flurbiprofen, ibuprofen,
ketorolac, naproxen, bromfenac, and suprofen.
[0225] Suitable examples of the aforementioned allergy medications
and antihistamines include, but are not limited to, loratadine,
hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine,
cyproheptadine, terfenadine, clemastine, triprolidine,
carbinoxamine, diphenylpyraline, phenindamine, azatadine,
tripelennamine, dexchlorphentramine, dexbrompheniramine,
methdilazine, and trimeprazine doxylamine, pheniramine, pyrilamine,
chlorcyclizine, thonzylamine, and derivatives thereof.
[0226] Suitable examples of the aforementioned antibiotics include,
but are not limited to, cefazolin, cephradine, cefaclor,
cephapirin, ceftizoxime, cefoperazone, cefotetan, cefutoxime,
cefotaxime, cefadroxil, ceftazidime, cephalexin, cephalothin,
cefamandole, cefoxitin, cefonicid, ceforanide, ceftriaxone,
cefadroxil, cephradine, cefuroxime, ampicillin, amoxicillin
cyclacillin ampicillin, penicillin G, penicillin V potassium,
piperacillin, oxacillin, bacampicillin, cloxacillin, ticarcillin,
azlocillin, carbenicillin, methicillin, nafcillin, erythromycin,
tetracycline, doxycycline, minocycline, aztreonam, chloramphenicol,
ciprofloxacin hydrochloride, clindamycin, metronidazole,
gentamicin, lincomycin, tobramycin, vancomycin, polymyxin B
sulfate, colistimethate, colistin, azithromycin, augmentin,
sulfamethoxazole, trimethoprim, and derivatives thereof.
[0227] In one embodiment, the implants of the present disclosure
utilize dexamethasone, fluticasone, bromfenac sodium, loteprednol
etabonate, or difluprednate.
[0228] In a particular embodiment, the implants of the present
disclosure utilize difluprednate.
[0229] Difluprednate
[0230] Difluprednate is a synthetic GR agonist, and a difluorinated
derivative of prednisolone. Difluprednate may be provided in a
micronized form in order to ensure consistent biopharmaceutical
properties when incorporated into the final dosage form. The
chemical structure of difluprednate is found below:
##STR00005##
[0231] Difluprednate undergoes deacetylation in vivo to 6.alpha.,
9-difluoroprednisolone 17-butyrate (deacetyl difluprednate; DFB),
an active metabolite of difluprednate.
[0232] Pharmaceutical Compositions
[0233] In embodiments, the pharmaceutical composition is comprised
of the biocompatible polymer matrix and at least one therapeutic
agent.
[0234] The biocompatible polymer matrix is comprised of polymers
meeting the desired characteristics. For example, desired
characteristics may include a specific therapeutic agent release
rate or a specific duration of action. The biocompatible polymer
matrix may be comprised of one polymer, two polymers, or many
polymers, such as three, four, five polymers, or more polymers.
[0235] In some embodiments, the compositions may comprise polymers
utilizing the same monomer, such as compositions comprising various
PEG homopolymers, or compositions comprising various PCL
homopolymers. However, even if the polymers of the composition
utilize the same monomer, the polymers may differ in other
characteristics, such as, for example, inherent viscosity or
molecular weight.
[0236] In other embodiments, the compositions may comprise polymers
utilizing different monomers, such as compositions comprising a PEG
homopolymer and a PCL homopolymer. However, even if the polymers of
the compositions utilize different monomers, the polymers may be
similar in other characteristics, such as for example, inherent
viscosity or molecular weight.
[0237] In one embodiment, the pharmaceutical composition comprises
a biocompatible polymer matrix and at least one therapeutic agent
homogeneously dispersed throughout the polymer matrix. Further, the
presently discussed pharmaceutical compositions comprising a
biocompatible polymer matrix and at least one therapeutic agent,
may, in certain embodiments, also exclude other polymers. That is,
in some embodiments, the aforementioned polymer matrix only
includes one polymer and active therapeutic agent.
[0238] In embodiments, the therapeutic agent is blended with the
biocompatible polymer matrix to form the pharmaceutical
composition. The amount of therapeutic agent used in the
pharmaceutical composition depends on several factors such as:
biocompatible polymer matrix selection, therapeutic agent
selection, rate of release, duration of release desired,
configuration of pharmaceutical composition, and ocular
pharmacokinetics, to name a few.
[0239] For example, the therapeutic agent may comprise
approximately 0.1 to approximately 60.0 weight percent of the
pharmaceutical composition. In some embodiments, the therapeutic
agent comprises approximately 5.0 to approximately 55.0 weight
percent of the pharmaceutical composition. In other embodiments,
the therapeutic agent comprises approximately 20.0 to approximately
55.0 weight percent of the pharmaceutical composition.
[0240] Implants having various compositions, sizes, and shapes were
fabricated and tested as set forth in the disclosure; however, it
will be appreciated that these are non-limiting examples of implant
designs contemplated by the present disclosure.
[0241] Fabrication of an Ocular Implant
[0242] Various methods may be used to produce the implants. Methods
include, but are not limited to, solvent casting, phase separation,
interfacial methods, molding, compression molding, injection
molding, extrusion, co-extrusion, heat extrusion, die cutting, heat
compression, and combinations thereof. In certain embodiments, the
implants are molded.
[0243] In particular embodiments, the implants of the present
disclosure are fabricated through the PRINT.RTM. particle
fabrication technology (Envisia Therapeutics Inc., North Carolina).
In particular, the implants are made by molding the materials
intended to make up the implants in polymeric mold cavities.
[0244] The molds can be polymer-based molds and the mold cavities
can be formed into any desired shape and dimension. Uniquely, as
the implants are formed in the cavities of the mold, the implants
are highly uniform with respect to shape, size, and composition.
Due to the consistency among the physical and compositional makeup
of each implant of the present pharmaceutical compositions, the
pharmaceutical compositions of the present disclosure provide
highly uniform release rates and dosing ranges. The methods and
materials for fabricating the implants of the present disclosure
are further described and disclosed in issued patents and pending
patent applications, each of which are incorporated herein by
reference in their entirety: U.S. Pat. Nos. 8,518,316; 8,444,907;
8,420,124; 8,268,446; 8,263,129; 8,158,728; 8,128,393; 7,976,759;
U.S. Pat. Application Publications Nos. 2013-0249138, 2013-0241107,
2013-0228950, 2013-0202729, 2013-0011618, 2013-0256354,
2012-0189728, 2010-0003291, 2009-0165320, 2008-0131692; and pending
U.S. application Ser. No. 13/852,683 filed Mar. 28, 2013 and Ser.
No. 13/950,447 filed Jul. 25, 2013.
[0245] The mold cavities can be formed into various shapes and
sizes. For example, the cavities may be shaped with curved edges,
sharp or square edges, circular or arched perimeters, flat sides,
substantially parallel sides, pointed ends, cylindrical, prism,
rectangular prism, triangular prism, pyramid, square pyramid,
triangular pyramid, cone, cylinder, torus, or rod. The cavities may
have the same shape or may have different shapes. In certain
aspects of the disclosure, the shapes of the implants are a
cylinder, rectangular prism, and rod. In a particular embodiment,
the implant is a rod having substantially a square, rectangular,
circular, or oval cross-section taken normal to the long axis of
the implant.
[0246] The mold cavities can be dimensioned from nanometer to
micrometer to millimeter dimensions and larger. For certain
embodiments of the disclosure, mold cavities are dimensioned in the
micrometer and millimeter range. For example, cavities may have a
smallest dimension of between approximately 50 nanometers and
approximately 750 .mu.m. In some aspects, the smallest mold cavity
dimension may be between approximately 1 .mu.m and approximately
500 .mu.m. In other aspects, the smallest mold cavity dimension may
be between approximately 225 .mu.m and approximately 400 .mu.m. For
example, mold cavities may have a largest dimension of between
approximately 1,000 .mu.m and approximately 10,000 .mu.m. In other
aspects, the largest mold cavity dimension may be between
approximately 2,000 .mu.m and approximately 6,000 .mu.m. In other
aspects, the largest mold cavity dimension may be between
approximately 4,000 .mu.m and approximately 6,000 .mu.m.
[0247] The implants can have an aspect ratio of width-to-length
from 1:1 to greater than 1:30. In some embodiments, the
width-to-length aspect ratio of the implant is between 1:2 to 1:25.
In some embodiments, the width-to-length aspect ratio of the
implant is between 1:5 to 1:20.In some embodiments, the
width-to-length aspect ratio of the implant is between 1:10 to
1:20. In some embodiments, the width-to-length aspect ratio of the
implant is between 1:15 to 1:20.
[0248] In one embodiment, a rod with dimensions of about 130
.mu.m.times.about 180 .mu.m.times.about 1,500 .mu.m
(H.times.W.times.L) is fabricated.
[0249] In one embodiment, a rod with dimensions of about 225
.mu.m.times.about 225 .mu.m.times.about 4,000 .mu.m
(H.times.W.times.L) is fabricated.
[0250] In another embodiment, a rod with dimensions of about 225
.mu.m.times.about 225 .mu.m.times.about 2,925 .mu.m
(H.times.W.times.L) is fabricated.
[0251] In another embodiment, a rod with dimensions of about 300
.mu.m.times.about 300 .mu.m.times.about 6,000 .mu.m
(H.times.W.times.L) is fabricated.
[0252] In another embodiment, a rod with dimensions of about 330
.mu.m.times.about 330 .mu.m.times.about 6,000 .mu.m
(H.times.W.times.L) is fabricated.
[0253] In a further embodiment, a rod with dimensions of about 400
.mu.m.times.about 400 .mu.m.times.about 6,000 .mu.m
(H.times.W.times.L) is fabricated.
[0254] Once fabricated, the implants may remain on an array for
storage, or may be harvested immediately for storage and/or
utilization. Implants may be fabricated using sterile processes,
may be sterilized after fabrication, or may be fabricated using
sterile processes and sterilized after fabrication. Thus, the
present disclosure contemplates kits that include a storage array
that has fabricated implants attached thereon. These storage
array/implant kits provide a convenient method for mass shipping
and distribution of the manufactured implants. In embodiments,
fabricated implants are packaged individually.
[0255] Delivery Devices
[0256] In embodiments, a delivery device may be used to insert the
implant into the eye or eyes for treatment or prevention of ocular
diseases.
[0257] Suitable devices can include a needle or needle-like
applicator. In some embodiments, the smallest dimension of an
implant may range from approximately 50 .mu.m to approximately 750
.mu.m, and therefore a needle or needle-like applicator with a
gauge ranging from approximately 19 to 27 may be utilized depending
on the cross-sectional dimension of the implant to inner diameter
of the needle as detailed elsewhere herein. The delivery device may
be a syringe with an appropriately sized needle or may be a
syringe-like device with a needle-like applicator,
[0258] For example, in embodiments in which an implant is sized and
structure to allow for administration in a 27 gauge needle (e.g.,
for a rod-shaped implant having dimensions of 225 .mu.m.times.about
225 .mu.m.times.about 2,925 .mu.m), the applicator needle has a
gauge of 27 and a length of 13 mm. In other embodiments in which an
implant is sized and structured to allow for administration in a 21
gauge needle (e.g. for a rod-shaped implant having dimensions of
300 .mu.m.times.about 300 .mu.m.times.about 6,000 .mu.m), the
applicator needle has a gauge of 21 and a length of 25 mm. In other
embodiments in which an implant is sized and structured to allow
for administration in a 25, 26, or 27 gauge needle (e.g., for a
rod-shaped implant having dimensions of 130 .mu.m.times.about 180
.mu.m/about 1,500 .mu.m), the applicator needle has a gauge of 25,
26, or 27 and length of 13 mm.
[0259] Delivery routes include punctual, intravitreal,
subconjunctival, intracameral, lens, intrascleral, fornix, anterior
sub-Tenon's, suprachoroidal, posterior sub-Tenon's, subretinal,
anterior chamber, and posterior chamber, to name a few.
[0260] In embodiments, an implant or implants are delivered to the
subconjunctival region of a patient's eye to prevent and/or treat
post-operative inflammation.
[0261] In embodiments, an implant or implants are delivered to the
intracameral region of a patient's eye to prevent and/or treat
post-operative inflammation.
[0262] Kits
[0263] In embodiments, the implant and delivery device may be
combined and presented as a kit for use.
[0264] The implant may be packaged separately from the delivery
device and loaded into the delivery device just prior to use.
[0265] Also, the implant may be loaded into the delivery device
prior to packaging. In this case, once the kit is opened, the
delivery device is ready for use.
[0266] Components may be sterilized individually and combined into
a kit, or may be sterilized after being combined into a kit.
[0267] Further, as aforementioned, a kit may include an array with
implants bound thereon.
[0268] Use of Ocular Implant for Treatment
[0269] In one aspect of the disclosure, there is presented a method
of preventing and/or treating post-operative inflammation. The
method comprises placing a biocompatible implant in an eye,
degrading or dissolving the implant, and releasing a therapeutic
agent which is effective to prevent and/or treat post-operative
inflammation.
[0270] In aspects of the disclosure, the eye is that of an animal.
For example, a dog, cat, horse, cow (or any agricultural livestock
or domesticated pet), or human.
[0271] In one aspect of the disclosure, there is presented a method
of preventing and/or treating post-operative pain. The method
comprises placing a biocompatible implant in an eye, degrading or
dissolving the implant, and releasing a therapeutic agent which is
effective to prevent and/or treat post-operative pain. The pain
treated or prevented may or may not be associated with
inflammation.
[0272] Corneal Thickening
[0273] Not to be bound by a particular theory, corneal thickening
(also known as corneal edema) refers to inflammation which is
induced in response to an ocular operation, such as surgery or
administration of an ocular implant. This effect is characterized
by the buildup of excess aqueous fluid in corneal tissue. Corneal
thickening is well known in the art to be a factor which hinders
the improvement of vision days after surgery. See Donnenfeld, et
al, Am. J. of Ophthalmology, Vol 152 (4); 2011: 609-617, which is
herein incorporated by reference in its entirety. Implants
comprising hydrophilic polymers, such as PEGs, can also induce
corneal thickening by causing cells located near the site of
administration to uptake excess aqueous fluid thereby becoming
inflamed. Thus, corneal thickening which occurs after ocular
administration of a hydrophilic polymer can exacerbate the corneal
thickening effect observed after cataract surgery and further
impair vision.
[0274] Corticosteroids are known to cause thinning of the cornea
after ocular administration. Thus, corticosteroids are typically
administered in an emulsified formulation after cataract surgery to
reduce corneal thickening. However, emulsified corticosteroid
formulations are not able to reduce corneal thickening to a
baseline at least a month after surgery. See Donnenfeld, et al, Am.
J. of Ophthalmology, Vol 152 (4); 2011: 609-617.
[0275] In some embodiments, the inventors discovered implant
formulations which overcome the limitations in the prior. Thus, in
some embodiments, the implants described herein are able to reduce
post-operation corneal thickening in the range of from about 1% to
about 100%. That is, in some embodiments, implants can be
formulated to offset post-operative corneal thickening.
[0276] In some embodiments, the implants described herein are able
to reduce corneal thickening to a baseline established prior to
surgery within about 30 days or less. Accordingly, in some
embodiments, the implants described herein can reduce
post-operative corneal thickening to a baseline within about 1 day
after administration of said implant. In other embodiments, the
implants described herein are able to reduce post-surgery corneal
thickening below a baseline established prior to surgery by about
1% to about 10%. In further embodiments, the implants can maintain
reduced post-operative corneal thickening for at least about 42
days. See FIG. 34.
[0277] In some embodiments, implants described herein can be
formulated to reduce corneal thickening observed after surgery
and/or after administration of an implant. See FIGS. 25A and 25B.
That is, in some embodiments, the implants described herein can be
formulated to prevent the corneal thickening effect associated with
administration of a hydrophilic implant. In some embodiments,
reducing the mass of the polymer matrix in the ocular implant can
decrease corneal thickening. Accordingly, in embodiments, the
amount of polymer matrix per implant is less than about 100 .mu.g,
e.g., less than about 40 .mu.g. In further embodiments, the percent
weight ratio (% w/w) of the polymer matrix relative to the
therapeutic agent is less than about 65%, e.g., less than about
45%.
[0278] Course of Treatment
[0279] Over the course of treatment, the biocompatible polymer
matrix degrades or dissolves releasing the therapeutic agent. Once
the therapeutic agent has been completely released, the polymer
matrix is expected to be degraded or dissolved. Complete polymer
matrix degradation may take longer than the complete release of the
therapeutic agent. Polymer matrix degradation may occur at the same
rate as the release of the therapeutic agent. Polymer matrix
dissolution provides for rapid release of the therapeutic
agent.
[0280] Current treatments for prevention and/or treatment of
post-operative inflammation require the patient to place drops in
their eyes each day. The pharmaceutical composition of the
disclosure is designed for release of an effective amount of
therapeutic agent, eliminating the need for daily drops. The
effective amount of the therapeutic agent may be provided through
sustained release or rapid release. For example, the pharmaceutical
composition may be designed to release an effective amount of
therapeutic agent for less than one day to approximately one day,
two days, three days, four days, five days, six days, seven days,
eight days, nine days, ten days, eleven days, twelve days, thirteen
days, fourteen days, 28 days, or longer. In aspects, the
pharmaceutical composition is designed to release an effective
amount of therapeutic agent for one day, two days, three days, five
days, seven days, ten days, twelve days, or longer. In other
aspects, the pharmaceutical composition is designed to release an
effective amount of therapeutic agent for seven days, ten days,
twelve days, or fourteen days.
[0281] Methods of the present disclosure for treating or preventing
a condition include inserting more than 5 implants to treat or
prevent the condition for more than 2 weeks. Methods of the present
disclosure for treating or preventing a condition include inserting
more than 10 implants to treat or prevent the condition for more
than 2 weeks. Methods of the present disclosure for treating or
preventing a condition include inserting more than 25 implants to
treat or prevent the condition for more than 2 weeks. Methods of
the present disclosure for treating or preventing a condition
include inserting more than 50 implants to treat or prevent the
condition for more than 2 weeks. Methods of the present disclosure
for treating or preventing a condition include inserting more than
100 implants to treat or prevent the condition for more than 2
weeks. Methods of the present disclosure for treating or preventing
a condition include inserting more than 500 implants to treat or
prevent the condition for more than 2 weeks. Methods of the present
disclosure for treating or preventing a condition include inserting
more than 1,000 implants to treat or prevent the condition for more
than 2 weeks. Methods of the present disclosure for treating or
preventing a condition include inserting more than 10,000 implants
to treat or prevent the condition for more than 2 weeks. Methods of
the present disclosure for treating or preventing a condition
include inserting more than 100,000 implants to treat or prevent
the condition for more than 2 weeks. Methods of the present
disclosure for treating or preventing a condition include inserting
more than 1,000,000 implants to treat or prevent the condition for
more than 2 weeks. The polymer composition and ratios of each
implant in these collections of implants can be varied between
implants within a single dose such that an aggregate degradation
profile of the collection of implants is achieved for delivery of
the therapeutic agent for greater than 2 weeks, greater than 1
month, greater than 3 months, greater than 4 months, greater than 6
months, greater than 9 months and greater than 12 months.
[0282] Delivery of implants disclosed herein may include delivery
through a 27 gauge needle or smaller. In some delivery methods, the
needle is 28 gauge, 29 gauge, 30 gauge, 31 gauge, 32 gauge, 33
gauge, or 34 gauge needle. In other aspects, a 21 or 22 gauge
needle is used. In other aspects, a 25 or 26 gauge needle is
used.
[0283] The following non-limiting examples illustrate certain
aspects of the present disclosure.
EXAMPLES
Example 1
Preparation of Polymer Matrix/Therapeutic Agent Blends
[0284] A series of polymer matrix/therapeutic agent blends were
prepared prior to molding implants. All blends contained
difluprednate as the therapeutic agent. Table 1 details the
composition of one series of blends.
TABLE-US-00001 TABLE 1 Polymer Matrix/Therapeutic Agent Blend
Ratios Polymer Matrix Therapeutic Target, % Agent PLGA PEG PCL
Target, % ID DLG1A 502H PEG3300 14K Difluprednate 642-64-1 40.0
10.0 50.0 642-64-2 60.2 9.8 30.0 642-64-3 70.0 30.0 642-64-4 50.0
50.0
Example 2
Fabrication of Molds
[0285] A series of molds of various dimensions were obtained for
the PRINT.RTM. particle replication technology from Envisia
Therapeutics Inc., North Carolina.
[0286] Molds obtained included molds with cavity sizes and shapes
as follows: a) a rod shape with dimensions of about 225
.mu.m.times.about 225 .mu.m.times.about 4,000 .mu.m, b) a rod shape
with dimensions of about 300 .mu.m.times.about 300
.mu.m.times.about 6,000 .mu.m, and c) a rod shape with dimensions
of about 400 .mu.m.times.about 400 .mu.m.times.about 6,000
.mu.m.
Example 3
Implant Fabrication
[0287] A series of implants were fabricated utilizing the polymer
matrix/therapeutic agent blends of Example 1 and the molds of
Example 2. Under aseptic conditions, a portion of polymer
matrix/therapeutic agent blend was spread over a PET sheet and was
heated on a hot plate for approximately 30 to 90 seconds until
fluid. Once heated, the blend was covered with the mold of Example
2 which had the desired dimensions. Light pressure was applied
using a hand roller to spread the blend over the mold area. The
mold/blend laminate was then passed through a commercially
available thermal laminator using the parameters in Table 2 below.
The blend flowed into the mold cavities and assumed the shape of
the mold cavities. The blend was allowed to cool to room
temperature creating individual implants in the mold cavities. The
mold was then removed leaving a two-dimensional array of implants
on the PET film. Individual implants were removed from the PET film
utilizing forceps.
TABLE-US-00002 TABLE 2 Implant Fabrication Conditions Process
Parameter Hot Plate 80-180 Temperature, .degree. C. Hot Plate Time,
30-180 seconds
[0288] Table 3 details the implants that were produced with the
blends of Example 1 and the molds of Example 2 using the
fabrication process of Example 3. The same ID used for the blend
was also used for the resulting implant.
TABLE-US-00003 TABLE 3 Implant Configurations ID Implant Dimensions
642-64-1 225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m 642-64-2
225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m 642-64-3 225 .mu.m
.times. 225 .mu.m .times. 4,000 .mu.m 642-64-4 225 .mu.m .times.
225 .mu.m .times. 4,000 .mu.m
Example 4
Analysis of Difluprednate Content
[0289] Individual implants were placed into 2 mL HPLC vials and
acetonitrile was added. The solution was diluted with an equal
volume of water. The difluprednate concentration was determined
using HPLC as described in Example 5 below. The mass of individual
implants was also determined. Table 4 details the test results for
the implants fabricated in Example 3.
TABLE-US-00004 TABLE 4 Difluprednate Content for Implants Diflu-
Difluprednate, .mu.g Overall Implant, .mu.g prednate ID AVE STDEV %
RSD AVE STDEV % RSD % 642- 129.2 5.8 4.5 252.2 14.1 5.6 51.2 64-1
642- 85.5 6.9 8.0 279.8 16.4 5.8 30.6 64-2 642- 60.3 1.5 2.5 211.2
6.7 3.2 28.6 64-3 642- 144.2 28.0 19.4 266.4 43.5 16.3 54.1
64-4
Example 5
HPLC Method for Determination of Difluprednate
[0290] Mobile phase A was prepared by combining approximately 900
mL water, approximately 100 mL acetonitrile, and approximately 1 mL
trifluoroacetic acid. Mobile phase B was prepared by combining
approximately 900 mL acetonitrile, approximately 100 mL water, and
approximately 1 mL trifluoroacetic acid. A series of standards were
prepared by diluting a known difluprednate standard.
[0291] For analysis conditions, the column was a Phenomenex Luna
Phenyl-hexyl, 3 .mu.m, 100.times.4.6 mm, flow rate was 1.0 mL per
minute, wavelength was 244 nm, temperature was 55.degree. C.,
injection volume was 5 .mu.L, and the run time was 14 minutes. The
gradient is detailed in Table 5.
TABLE-US-00005 TABLE 5 HPLC Gradient for Difluprednate Analysis
Time, minutes Mobile Phase A, % Mobile Phase B, % 0 70 30 1 70 30 9
30 70 9.1 70 30 14 70 30
[0292] To determine therapeutic agent content in an implant, the
measured .mu.g/mL determined from the response associated with the
standard curve was multiplied by the volume used to dissolve the
implant.
Example 6
In Vitro Difluprednate Release Studies
[0293] In vitro release of difluprednate was determined for the
implants of Example 3. In this study, single implants were placed
into HPLC vials and were incubated in a volume of 1.times.PBS
(phosphate buffered saline) containing 1% sodium dodecyl sulfate
media at 37.degree. C. At each time point of interest, the media
was removed for analysis. The media was then replaced with fresh
media. The media that was removed was analyzed for difluprednate
released via the HPLC method of Example 5.
[0294] FIGS. 1A and 1B depict the results of the study
graphically.
Example 7
Preparation of Polymer Matrix/Therapeutic Agent Blends
[0295] A series of polymer matrix/therapeutic agent blends were
prepared prior to molding implants. All blends contained
difluprednate as the therapeutic agent. Table 6 details the
composition of one series of blends.
TABLE-US-00006 TABLE 6 Polymer Matrix/Therapeutic Agent Blend
Ratios Polymer Matrix Therapeutic Target, % Agent PEG PCL Target, %
ID PEG3300 2K 14K Difluprednate 642-69-1 50.0 50.0 642-69-2 25.0
25.0 50.0 642-69-3 50.0 50.0 642-69-4 10.0 40.0 50.0 642-69-5 25.0
25.0 50.0
[0296] Table 7 details the implants that were produced with the
blends of Example 7 and the molds of Example 2 using the
fabrication process of Example 3. The same ID used for the blend
was also used for the resulting implant.
TABLE-US-00007 TABLE 7 Implant Configurations ID Implant Dimensions
642-69-1 225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m 642-69-2
225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m 642-69-3 225 .mu.m
.times. 225 .mu.m .times. 4,000 .mu.m 642-69-4 225 .mu.m .times.
225 .mu.m .times. 4,000 .mu.m 642-69-5 400 .mu.m .times. 400 .mu.m
.times. 6,000 .mu.m
[0297] Implants were analyzed for difluprednate content according
to Example 4 and Example 5. Results for the implants of Example 7
are shown in Table 8.
TABLE-US-00008 TABLE 8 Difluprednate Content for Implants Diflu-
Difluprednate, .mu.g Overall Implant, .mu.g prednate ID AVE STDEV %
RSD AVE STDEV % RSD % 642- 99.2 3.0 3.0 206.0 4.5 2.2 48.1 69-1
642- 105.0 4.6 4.4 206.5 6.7 3.3 50.1 69-2 642- 115.1 6.5 5.7 227.0
7.6 3.3 51.6 69-3 642- 102.9 2.7 2.6 220.0 8.3 3.8 46.7 69-4 642-
630.5 56.3 8.9 1,197.8 95.3 8.0 51.7 69-5
Example 8
In Vitro Difluprednate Release Studies
[0298] In vitro release of difluprednate was determined for the
implants of Example 7. Implants were testing according to the
method of Example 6.
[0299] FIGS. 2A through 2F detail particular results from studies
utilizing a single implant.
[0300] FIG. 2A shows the percent difluprednate released as a
function of time (days) for four of the samples under study. FIG.
2B shows the percent of difluprednate released as a function of
time (days) for two of the samples under study. The data
demonstrates that for the blends under investigation, for example
642-69-4 and 642-69-5, a smaller implant containing about the same
percentage therapeutic agent content releases the therapeutic agent
more rapidly on a percentage basis when compared to a larger
implant. Also, the data demonstrates that use of a higher molecular
weight PCL slows the release of therapeutic agent. When combining a
higher and lower molecular weight PCL, the release of therapeutic
agent is intermediate to that of each respective PCL. To increase
the release rate of higher molecular weight PCL samples, PEG can
also be utilized. The data demonstrates that the percentage
released for the therapeutic agent can be adjusted.
[0301] Further details of the study are shown in FIGS. 2C and
2D.
[0302] FIGS. 2C and 2D show the release rate (paiday) of
difluprednate as a function of time (days).
[0303] The data demonstrates that for the blends under
investigation, for example 642-69-4 and 642-69-5, a smaller implant
containing about the same percentage therapeutic agent but an
overall lower therapeutic agent content releases the therapeutic
agent for a shorter time period when compared to a larger implant.
Also, the data demonstrates that use of a higher molecular weight
PCL slows the release of therapeutic agent, allowing the implant to
release therapeutic agent for a longer time span. When combining
use of a higher and lower molecular weight PCL into the same
implant configuration, the release rate of therapeutic agent is
intermediate to that of each respective PCL To increase the release
rate of higher molecular weight PCL samples, PEG can also be
utilized. The data demonstrates that the release rate for the
therapeutic agent can be adjusted.
[0304] Further details of the study are shown in FIGS. 2E and
2F.
[0305] FIG. 2E shows the cumulative therapeutic agent released as a
function of time. The data in FIG. 2F shows a subset of the samples
all having a 225 .mu.m.times.225 .mu.m.times.4,000 .mu.m
configuration.
Example 9
Implants Utilized for In Vivo Studies
[0306] A twelve day in vivo study utilizing New Zealand White
Rabbits was conducted to determine the ocular tolerability and also
determine residual difluprednate in the implant at the study
termination. Table 9 details the IDs of the implants, number of
implants utilized for dosing, and number of eyes dosed for the
studies. Tables in the previous examples provide information as to
composition and dimension for the implants. Topical administration
of DUREZOL.RTM. (difluprednate ophthalmic emulsion) (Alcon
Laboratories, Inc.) was used as a positive control. The dosing
paradigm for the positive control was one drop per eye, four times
daily for the duration of the study. For a negative control the
surgery was conducted, but no implant was used. Implants were
placed either subconjunctivally or intracamerally. For
subconjunctival placement, the implants were either directly
injected into the subconjunctival tissue or a pocket was created in
the subconjunctival region through a 1-2 mm incision in the
conjunctiva at the place of interest. An appropriately sized needle
was used to deliver the implant directly into the tissue or into
the pocket. The pocket was able to contain up to three implants.
For eyes containing greater than three implants, the appropriate
number of pockets were created (i.e. two pockets to hold two
implants each for a total of four implants delivered). For
intracameral placement, implants were delivered through the limbus
to the intracameral location using an appropriately sized needle as
described elsewhere herein.
[0307] The Hackett-McDonald Scoring System was used to determine
the Total Ocular Exam Score. A "perfect score" is equal to 0;
however, a composite score that does not equal zero does not
indicate a clinically unacceptable pharmaceutical composition.
Residual difluprednate was determined in the retrieved implants
using the method described in Example 4 and Example 5.
[0308] FIG. 3 depicts the Total Ocular Exam Score for the implants
under study. Transient spikes post-procedure were observed on Days
3 and 7. As expected, the negative control has the highest score
throughout the study duration. However, at least one sample,
642-69-5 (3 implants) had a Total Ocular Exam Score below that of
the positive control at least one time interval.
[0309] Table 10 and FIG. 4 depict results for the residual
difiuprednate determination. Note, animal 34L, one of the four
implants fractured upon insertion. As a result, the theoretical
dose is an estimate, not an actual value. At least two of the
samples delivered a therapeutic agent dose with a relative standard
deviation of less than 10% over the 12 day study. FIG. 4 depicts
the data graphically.
TABLE-US-00009 TABLE 9 In Vivo Implants Therapeutic Therapeutic
Agent Agent Total Implants Eyes Content/ Content/ Dosed/Eye Dosed
Implant Dose Delivery ID # # .mu.g .mu.g Route 642-69-2 4 4 105 420
Subcon- junctival 642-69-2 2 4 105 210 Intra- cameral 642-69-5 3 4
636 1908 Subcon- junctival Positive Not 4 60 60 Topical Control
Appli- drops cable Negative Not 4 0 0 No Control Appli- implant
cable
TABLE-US-00010 TABLE 10 Delivered and Retrieved Difluprednate for
In Vivo Study Therapeutic Agent Therapeutic Therapeutic Therapeutic
Total Agent Agent Agent Content/Dose Recovered Recovered Delivered
ID Animal .mu.g .mu.g % % 642-69-2 34L 385 130.4 33.9 66.1 34R 420
170.4 40.6 59.4 35L 420 106.4 25.3 74.7 35R 420 230.5 54.9 45.1
Average 38.7 61.3 STDEV 12.5 12.5 642-69-2 36L 210 151.2 72.0 28.0
36R 210 144 68.6 31.4 37L 210 152.6 72.7 27.3 37R 210 141.3 67.3
32.7 Average 70.1 29.9 STDEV 2.6 2.6 642-69-5 38L 1892 1402.4 74.1
25.9 38R 1892 1390.8 73.5 26.5 39L 1892 1365.3 72.2 27.8 39R 1892
1313.9 69.4 30.6 Average 72.3 27.7 STDEV 2.1 2.1
Example 10
Polymer Matrix/Therapeutic Agent Blend Ratios
[0310] A series of polymer matrix/therapeutic agent blends were
prepared prior to molding implants. All blends contained
dilluprednate as the therapeutic agent. Table 11 details the
composition of one series of blends.
TABLE-US-00011 TABLE 11 Polymer Matrix/Therapeutic Agent Blend
Ratios Therapeutic Polymer Matrix Target, % Agent PEG PCL Target, %
ID PEG35K PEG100K 2K 14K 45K Glycerol Difluprednate 0053-1-1 34.3
14.7 8.8 8.8 3.5 30.0 0053-1-2 14.7 6.3 22.8 22.8 3.5 30.0 0053-1-3
22.1 9.5 17.5 17.5 3.5 30.0 0053-1-4 22.1 9.5 17.5 17.5 3.5 30.0
0053-1-5 14.7 6.3 22.8 22.8 3.5 30.0 0053-1-6 52.5 14.0 3.5 30.0
0053-4-1 34.3 14.7 8.8 8.8 3.5 30.0 0053-4-2 14.7 6.3 22.8 22.8 3.5
30.0 0053-4-3 22.1 9.5 17.5 17.5 3.5 30.0 0053-4-4 52.5 14.0 3.5
30.0 0053-4-5 24.5 10.5 31.5 3.5 30.0 0053-4-6 14.7 6.3 45.5 3.5
30.0 0053-4-7 66.5 3.5 30.0 0053-4-8 10.5 4.5 32.5 2.5 50.0
0053-4-9 5.3 2.3 40.0 3.5 50.0 0053-4-10 66.5 3.5 30.0 0053-4-11
14.7 6.3 45.5 3.5 30.0 0053-4-12 24.5 10.5 31.5 3.5 30.0 0053-4-13
27.0 11.6 14.0 14.0 3.5 30.0
Example 11
Implant Fabrication
[0311] Table 12 details the implants that were produced with the
blends of Example 10 and the molds of Example 2 using the
fabrication process of Example 3. The same ID used for the blend
was also used for the resulting implant.
TABLE-US-00012 TABLE 12 Implant Configurations ID Implant
Dimensions 0053-1-1 225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m
0053-1-2 225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m 0053-1-3
225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m 0053-1-4 225 .mu.m
.times. 225 .mu.m .times. 4,000 .mu.m 0053-1-5 225 .mu.m .times.
225 .mu.m .times. 4,000 .mu.m 0053-1-6 225 .mu.m .times. 225 .mu.m
.times. 4,000 .mu.m 0053-4-1 400 .mu.m .times. 400 .mu.m .times.
6,000 .mu.m 0053-4-2 400 .mu.m .times. 400 .mu.m .times. 6,000
.mu.m 0053-4-3 400 .mu.m .times. 400 .mu.m .times. 6,000 .mu.m
0053-4-4 400 .mu.m .times. 400 .mu.m .times. 6,000 .mu.m 0053-4-5
400 .mu.m .times. 400 .mu.m .times. 6,000 .mu.m 0053-4-6 400 .mu.m
.times. 400 .mu.m .times. 6,000 .mu.m 0053-4-7 400 .mu.m .times.
400 .mu.m .times. 6,000 .mu.m 0053-4-8 400 .mu.m .times. 400 .mu.m
.times. 6,000 .mu.m 0053-4-9 400 .mu.m .times. 400 .mu.m .times.
6,000 .mu.m 0053-4-10 225 .mu.m .times. 225 .mu.m .times. 4,000
.mu.m 0053-4-11 225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m
0053-4-12 225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m 0053-4-13
400 .mu.m .times. 400 .mu.m .times. 6,000 .mu.m
Example 12
Analysis of Difluprednate Content
[0312] Implants were analyzed for difluprednate content according
to Example 4 and Example 5. The mass of individual implants was
also determined. Table 13 details the test results for the implants
fabricated in Example 11.
TABLE-US-00013 TABLE 13 Difluprednate Content for Implants
Difluprednate, .mu.g Overall Implant, .mu.g Difluprednate ID AVE
STDEV % RSD AVE STDEV % RSD % 0053-1-1 73.9 4.1 5.5 222.1 22.5 10.1
33.3 0053-1-2 58.2 2.2 3.8 195.4 3.6 1.8 29.8 0053-1-3 59.4 1.8 3.0
209.9 5.1 2.4 28.3 0053-1-4 56.0 1.7 3.1 199.5 3.7 1.8 28.1
0053-1-5 57.5 1.8 3.1 192.0 3.5 1.8 30.1 0053-1-6 71.3 4.8 6.7
236.1 9.5 4.0 30.2 0053-4-1 296.1 13.6 4.6 1,255.2 93.2 7.4 24.3
0053-4-2 298.4 32.2 10.8 1,139.3 129.3 11.3 26.1 0053-4-3 275.1
48.3 17.6 1,057.6 127.9 12.1 26.5 0053-4-4 321.7 33.4 10.4 1,326.1
161.1 12.1 26.7 0053-4-5 325.2 33.7 10.4 1,172.0 119.0 10.2 27.8
0053-4-6 305.0 21.1 6.9 1,114.8 102.3 9.2 26.9 0053-4-7 264.0 18.7
7.1 1,002.3 95.0 9.5 26.0 0053-4-8 495.9 71.9 14.5 1,143.9 140.8
12.3 43.8 0053-4-9 474.1 45.9 9.7 1,100.5 113.4 10.3 45.0 0053-4-10
45.3 2.6 5.7 191.2 7.5 3.9 23.7 0053-4-11 54.2 2.6 4.8 202.5 8.0
3.9 26.8 0053-4-12 58.0 1.8 3.0 224.1 3.8 1.7 25.9 0053-4-13 292.7
20.7 7.1 1096.2 116.1 10.6 26.8
Example 13
In Vitro Difluprednate Release Studies
[0313] The in vitro release of difluprednate was determined for the
implants of Example 11 according to the method of Example 6. Test
results are shown in FIG. 5A through FIG. 5C. FIG. 5A shows the
percent difluprednate released as a function of time (days) for
samples under study. FIG. 5B shows the release rate (.mu.g/day) for
samples under study. Note that sample 0053-01-1 is not shown in
this figure due to the rapid release of difluprednate. FIG. 5C
shows the cumulative difluprednate (.mu.g) released for samples
under study. Test results are also shown in FIG. 6A through FIG.
6C. FIG. 6A shows the percent difluprednate released as a function
of time (days) for samples under study. FIG. 6B shows the release
rate (.mu.g/day) for samples under study. FIG. 6C shows the
cumulative difluprednate (.mu.g) released for samples under
study.
[0314] All implants in FIGS. 5A-5C contained approximately 30wt %
difluprednate and were about 225 .mu.m.times.225 .mu.m.times.4,000
.mu.m in size. Most notable, is that use of increased levels of
PEG35K or increased levels of PEG35K in conjunction with a
PCL2K/PCL4K blend lead to rapid difluprednate release.
[0315] All samples in FIG. 6A through 6C also contained
approximately 30wt % difluprednate. Most samples were configured to
about 400 .mu.m.times.400 .mu.m.times.6,000 .mu.m in size, however,
00053-4-10, 00053-4-11, and 00053-4-12 were configured to about 225
.mu.m.times.225 .mu.m.times.4,000 .mu.m. Samples 00053-4-5 and
00053-4-12; 00053-4-6 and 00053-4-11; 00053-4-7 and 00053-4-10 were
similar composition pairs but differed in configuration.
Example 14
Implants Utilized for In Vivo Studies
[0316] A thirteen day in vivo study utilizing New Zealand White
Rabbits was conducted to determine the ocular tolerability and
effect on induced ocular inflammation over the course of the study
for a select group of samples in Example 11. Table 14 details the
IDs of the implants, number of implants utilized for dosing, and
number of eyes dosed for the studies. Tables in the previous
examples provide information as to composition and dimension for
the implants. Topical administration of DUREZOL.RTM. (difluprednate
ophthalmic emulsion) (Alcon Laboratories, Inc.) was used as a
positive control. The dosing paradigm was one drop per eye, four
times daily for the duration of the study. For a negative control
the surgery was conducted and a placebo implant (no difluprednate)
was inserted.
[0317] Implants were placed subconjunctivally as described in
Example 9. Two models were evaluated: paracentesis and corneal
incision. In the paracentesis model, approximately 100 .mu.L
aqueous humor was withdrawn from samples on days 2 and 6. In the
corneal incision model, 100 .mu.L aqueous humor was withdrawn from
animals on day 2. Additionally, corneal incision model groups had a
2.7 mm incision in the superior cornea sutured with 8-0 or 9-0
Vicryl on day 2.
[0318] The Total Ocular Exam Score was also scored as described in
Example 9. All corneal incision groups had any scoring related to
inflammation surrounding sutures omitted from the Total Ocular Exam
Score. FIG. 7 depicts the results of the ocular examinations.
TABLE-US-00014 TABLE 14 In Vivo Implants Therapeutic Agent Implants
Eyes Therapeutic Agent Total Dosed/Eye Dosed Content/Implant
Content/Dose ID # # .mu.g .mu.g Method of Delivery Placebo 3 0 0
Subconjunctival Injection Implant Positive 0 50 50 Topical Drops
Control 53-1-3 2 59.5 118.9 Subconjunctival Injection 53-1-3 4 59.5
237.8 Subconjunctival Injection 53-4-4 2 343 686 Subconjunctival
Injection 53-4-13 3 349 1046 Subconjunctival Injection 53-4-8 1 492
492 Subconjunctival Injection 53-4-9 ~1.9 485 922 Subconjunctival
Injection 53-4-9 ~3.6 496 1786 Subconjunctival Injection 53-4-6 2
or 3 393 786 Subconjunctival Injection Placebo 3 0 0
Subconjunctival Injection Implant Positive 0 50 50 Topical Drops
Control 53-4-13 2.75 325 894 Subconjunctival Injection 53-4-8 1 569
569 Subconjunctival Injection
Example 15
Polymer Matrix/Therapeutic Agent Blend Ratios
[0319] A series of polymer matrix/therapeutic agent blends were
prepared prior to molding implants. All blends contained
dilluprednate as the therapeutic agent. Table 15 details the
composition of one series of blends.
TABLE-US-00015 TABLE 15 Polymer Matrix/Therapeutic Agent Blend
Ratios Polymer Matrix Therapeutic Target, % Agent PEG Target, % ID
PEG35K PEG100K PEG1MM Glycerol Difluprednate 00053.23-1 45.0 5.0
50.0 00053-23.2 50.0 50.0 00053-23-3 50.0 50.0 00053-23-4 49.0 21.0
30.0 00053-23-5 35.0 15.0 50.0 00053-23-6 35.0 15.0 50.0 00053-28-1
48.7 20.9 30.4 00053-28-2 34.9 15.0 50.1 00053-28-3 50 50.0
Example 16
Implant Fabrication
[0320] Table 16 details the implants that were produced with the
blends of Example 15, the molds of Example 2, and using the
fabrication process of Example 3. The same ID used for the blend
was also used for the resulting implant.
TABLE-US-00016 TABLE 16 Implant Configurations ID Implant
Dimensions 00053.23-1 225 .mu.m .times. 225 .mu.m .times. 4,000
.mu.m 00053-23.2 225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m
00053-23-3 225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m
00053-23-4 225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m
00053-23-5 225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m
00053-23-6 225 .mu.m .times. 225 .mu.m .times. 4,000 .mu.m
00053-28-1 300 .mu.m .times. 300 .mu.m .times. 6,000 .mu.m
00053-28-2 300 .mu.m .times. 300 .mu.m .times. 6,000 .mu.m
00053-28-3 300 .mu.m .times. 300 .mu.m .times. 6,000 .mu.m
Example 17
Analysis of Difluprednate Content
[0321] The difluprednate concentration of the implants was
determined via detection of using HPLC as described in Example 5.
The mass of individual implants was also determined. Table 17
details the test results for the implants fabricated in Example
16.
TABLE-US-00017 TABLE 17 Difluprednate Content for Implants
Difluprednate, .mu.g Overall Implant, .mu.g Difluprednate ID AVE
STDEV % RSD AVE STDEV % RSD % 00053.23-1 90.6 2.9 3.3 203.7 6.5 3.2
44.5 00053-23.2 93.7 4.2 4.4 227.6 11.5 5.1 41.2 00053-23-3 92.0
0.9 1.0 228.2 1.3 0.6 40.3 00053-23-4 51.1 1.1 2.1 218.4 1.5 0.7
23.4 00053-23-5 89.0 2.9 3.3 234.9 3.9 1.7 37.9 00053-23-6 91.8 2.5
2.7 245.3 2.9 1.2 37.4 00053-28-1 215.9 15.3 7.1 812.4 80.2 9.9
26.6 00053-28-2 384.3 12.0 3.1 821.4 22.2 2.7 46.8 00053-28-3 385.7
32.1 8.3 818.8 64.5 7.9 47.1
Example 18
Implants Utilized for In Vivo Studies
[0322] A twenty-four day in vivo study utilizing New Zealand White
Rabbits was conducted to determine the ocular tolerability and
effect on induced inflammation over the course of the study for a
select group of samples in Example 9. Table 18 details the IDs of
the implants, number of implants utilized for dosing, and number of
eyes dosed for the studies. Tables in the previous examples provide
information as to composition and dimension for the implants.
Topical administration of DUREZOL.RTM. (difluprednate ophthalmic
emulsion) (Alcon.RTM. Laboratories, Inc.) was used as a positive
control. The dosing paradigm for the positive control was one drop
per eye, four times daily for the duration of the study. For a
negative control the surgery was conducted and a placebo implant
containing no difluprednate was inserted.
[0323] Implants were placed subconjunctivally as described in
Example 9, Two models were evaluated: paracentesis and corneal
incision. In the paracentesis model, approximately 100 .mu.L
aqueous humor was withdrawn from samples on days 2 and 6. In the
corneal incision model, 100 .mu.L aqueous humor was withdrawn from
samples on day 2. Additionally, corneal incision model groups had a
2.7 mm incision in the superior cornea sutured with 8-0 or 9-0
Vicryl on day 2.
[0324] The Total Ocular Exam Score was also scored as described in
Example 9. All corneal incision groups had any scoring related to
inflammation surrounding sutures omitted from the Ocular Safety
Index. FIG. 8 depicts the results of the ocular examinations.
TABLE-US-00018 TABLE 18 In Vivo Implants Implants Eyes Therapeutic
Agent Therapeutic Agent Dosed/Eye Dosed Content/Implant Total
Content/Dose ID # # .mu.g .mu.g Placebo Implant 2 6 0 0 Positive
Control (Topical) 0 6 50 200 Positive Control (Injected) 0 6 50 50
53-23-5 2 6 105 210 53-28-1 2 6 216 432 53-28-2 3 6 384 1152
53-28-3 3 6 386 1158 53-4-8 2 6 556 1112
Example 19
ENV905 Difluprednate Ophthalmic Implant Studies
[0325] The present example demonstrates an embodiment of the
disclosure, termed ENV905, which is a difluprednate ophthalmic
implant for the treatment of inflammation and pain associated with
ocular surgery.
[0326] ENV905 (difluprednate) ophthalmic implant is an injectable
difluprednate implant formulation using a biocompatible
polyethylene glycol (PEG)-based drug delivery system. The implant
is designed for ophthalmic administration via subconjunctival (SCJ)
or intracameral (IC) injection, with a single dose administered
following ocular surgery targeting duration of action of 28 days.
The PEG-based drug delivery system is comprised of a blend of two
PEGs that function as both diluent and binder, and was designed for
rapid dissolution of the implant and concurrent release of
difluprednate following administration.
[0327] The bioavailability and sustained therapeutic effect of
ENV905 over 28 days is governed by multiple factors, including
route of administration and the physicochemical properties of the
drug substance difluprednate.
[0328] The present example illustrates the functionality of various
formulations of ENV905 ocular implants. Included in the various
embodiments of ENV905 ocular implants tested are ENV.sup.-905-1
(also designated by sample ID No. "115-8-7") and ENV905-2 (also
designated by sample ID No. "115-16-1").
[0329] Each formulation was designed according to its intended
route of administration, either IC (ENV905-1) or SCJ (ENV905-2).
These two embodiments are designed to decrease ocular inflammation
and pain for 28 days following a single administration via SCJ or
IC injection, with the intended range of doses from approximately
40 to 80 .mu.g (IC) or 400 to 800 .mu.g (SCJ) difluprednate.
[0330] Characterization and Overview of ENV905
[0331] ENV905 is a biocompatible implant formulation containing the
corticosteroid difluprednate in a PEG-based drug delivery system.
ENV905 is formulated as a solid, rod-shaped implant of dimensions
between 225-350 .mu.m in width by 2,925-6,000 .mu.m in length.
[0332] The aforementioned ENV905-1 formulation embodiment is
designed for intracameral delivery into the anterior chamber of the
eye. The IC implant ENV905-1 will enable targeted delivery of
difluprednate directly into the anterior chamber, providing a
potentially dose-sparing effect compared to DUREZOL.RTM.. The IC
ENV905-1 implant was designed to rapidly disintegrate in the
anterior chamber, providing a therapeutic effect over approximately
28 days.
[0333] The aforementioned ENV905-2 formulation embodiment is
designed for implantation in the subconjunctival space. The SCJ
implant ENV905-2 was designed to rapidly disintegrate in the
subconjunctival space, providing a therapeutic effect over
approximately 28 days.
[0334] The two formulation embodiments differ in size and dose of
difluprednate, while maintaining the same formulation
characteristics of PEG excipients. The characteristics of these
implants can be found, inter alia, in the below Tables 19 and
20.
TABLE-US-00019 TABLE 19 ENV905-1: Intracameral Ophthalmic Implant
Formulation (Nominal Ranges) ENV905-1 Intracameral Implant
Formulation Nominal Dimensions: 225 .mu.m .times. 225 .mu.m .times.
2,925 .mu.m Amount Component/Property Function (.mu.g/implant) %
w/w Difluprednate Active 24 to 56 15 to 35 Total PEG (PEG 3,350 and
Diluent/ 104 to 136 65 to 85 PEG 100,000) Binder PEG 3,350 11.4 to
15.0 7.2 to 9.4 PEG 100,000 92.6 to 121.0 57.9 to 75.7 Ratio of PEG
3,350/PEG 11%/89% w/w 100,000 Total Implant Mass -- 128 to 192
--
TABLE-US-00020 TABLE 20 ENV905-2: Subconjunctival Ophthalmic
Implant Formulation (Nominal Ranges) ENV905-2 Subconjunctival
Implant Formulation Nominal Dimensions: 300 .mu.m .times. 300 .mu.m
.times. 6,000 .mu.m Amount Component/Property Function
(.mu.g/implant) % w/w Difluprednate Active 320 to 480 40 to 60
Total PEG (PEG 3,350 and Diluent/ 320 to 480 40 to 60 PEG 100,000)
Binder PEG 3,350 35.2 to 52.8 4.4 to 6.6 PEG 100,000 284.8 to 427.2
35.6 to 53.4 Ratio of PEG 3,350/PEG 11%/89% w/w 100,000 Total
Implant Mass -- 640 to 960 --
TABLE-US-00021 TABLE 21 ENV905-3: Intracameral Ophthalmic Implant
Formulation (Nominal Ranges) ENV905-3 Intracameral Implant
Formulation Nominal Dimensions: 225 .mu.m .times. 225 .mu.m .times.
2,925 .mu.m Amount Component/Property Function (.mu.g/implant) %
w/w Difluprednate Active 16 to 24 10 to 15 Total PEG (PEG 3,350 and
Diluent/ 136 to 144 85 to 90 PEG 100,000) Binder PEG 3,350 15.0 to
15.8 9.4 to 9.9 PEG 100,000 121.0 to 128.2 75.7 to 80.1 Ratio of
PEG 3,350/PEG 11%/89% w/w 100,000 Total Implant Mass -- 152 to 168
--
TABLE-US-00022 TABLE 22 ENV905-4: Intracameral Ophthalmic Implant
Formulation (Nominal Ranges) ENV905-4 Intracameral Implant
Formulation Nominal Dimensions: 225 .mu.m .times. 225 .mu.m .times.
2,925 .mu.m Amount Component/Property Function (.mu.g/implant) %
w/w Difluprednate Active 8 to 12 5.0 to 7.5 Total PEG (PEG 3,350
and Diluent/ 148 to 152 92.5 to 95.0 PEG 100,000) Binder PEG 3,350
16.3 to 16.7 10.2 to 10.5 PEG 100,000 131.7 to 135.3 82.3 to 84.6
Ratio of PEG 3,350/PEG 11%/89% w/w 100,000 Total Implant Mass --
156 to 164
TABLE-US-00023 TABLE 23 ENV905-5: Intracameral Ophthalmic Implant
Formulation (Nominal Ranges) ENV905-5 Intracameral Implant
Formulation Nominal Dimensions: 130 .mu.m .times. 180 .mu.m .times.
1,500 .mu.m Amount Component/Property Function (.mu.g/implant) %
w/w Difluprednate Active 16 to 24 29.6 to 44.4 Total PEG (PEG 3,350
and Diluent/ 30 to 38 55.6 to 70.4 PEG 100,000) Binder PEG 3,350
3.3 to 4.2 6.1 to 7.7 PEG 100,000 26.7 to 33.8 49.4 to 62.6 Ratio
of PEG 3,350/PEG 11%/89% w/w 100,000 Total Implant Mass -- 46 to
62
[0335] ENV905 implants can be loaded into the needle of a
single-use implant applicator and delivered directly into either
the subconjunctival space or the anterior chamber. ENV905 was
designed to deliver therapeutic levels of difluprednate for
approximately 28 days in certain aspects.
[0336] ENV905 implants, of various configurations, have been well
tolerated in efficacy and tolerability studies in albino rabbits
following administration by their respective routes of delivery.
This generalization will be supported by the below data.
[0337] Following subconjunctival insertion, ENV905-2 implants
remain at the insertion site, cause no apparent discomfort, and
rapidly disintegrate. Following IC insertion, ENV905-1 implants
localize to the inferior iridocorneal angle upon insertion, remain
largely immobile, and quickly disintegrate. ENV905 has been shown
to decrease ocular inflammation in New Zealand white (NEN) rabbit
models of post-operative inflammation, with excellent safety and
tolerability profiles following both SCJ and IC administration.
[0338] Potential Mechanism of Action for ENV905 Embodiments
[0339] Without wishing to be bound to a particular mechanistic
theory of action, the following description provides one possible
mechanism of action for the ENVA905 ocular implants disclosed
herein.
[0340] Corticosteroids inhibit the inflammatory response to a
variety of inciting agents. They inhibit edema, fibrin deposition,
capillary dilation, leukocyte migration, capillary proliferation,
fibroblast proliferation, deposition of collagen, and scar
formation associated with inflammation.
[0341] Corticosteroid activity is mediated by intracellular
activation of GR. Binding of the corticosteroid ligand results in
translocation of the ligand-bound GR from the cell cytosol into the
nucleus, where it functions as a transcription factor and binds to
the glucocorticoid response elements in the promoter regions of
responsive genes or interacts directly with other transcription
factors. The actions results in consequent anti-inflammatory
effects due to down-regulation of pro-inflammatory molecule
production.
[0342] In the eye, corticosteroids are thought to act by the
induction of phospholipase A2 inhibitory proteins, collectively
called lipocortins. It is postulated that these proteins control
the biosynthesis of potent mediators of inflammation such as
prostaglandins and leukotrienes by inhibiting the release of their
common precursor arachidonic acid. Arachidonic acid is released
from membrane phospholipids by phospholipase A2. Difluprednate is
structurally similar to other corticosteroids (DUREZOL.RTM. Package
Insert), DUREZOL.RTM. is a topical corticosteroid that is indicated
for the treatment of inflammation and pain associated with ocular
surgery as well as the treatment of endogenous anterior uveitis.
DUREZOL.RTM. is formulated as a 0.05% difluprednate sterile
preserved emulsion, and the treatment regimen is instillation of
one drop into the conjunctival sac 4 times daily for 14 days,
followed by a tapering regimen as clinically indicated.
[0343] The ENV905-1 and ENV905-2 embodiments can decrease ocular
inflammation and/or pain for 28 days following a single
administration via SCJ or IC injection, by effectively delivering
difluprednate to targeted areas of the eye, rather than via the
problematic topical application required for DUREZOL.RTM..
[0344] Nonclinical Pharmacology of Difluprednate in Ocular
Formulations
[0345] Difluprednate, a corticosteroid pro-drug of the active
metabolite 6.alpha.,9-difluoroprednisolone 17-butyrate (DFB), is
marketed as a 0.05% sterile preserved emulsion for topical ocular
delivery. DUREZOL.RTM. is administered as a 4 times per day drop
(approximately 100 .mu.g per day) in patients recovering from
ocular surgery or patients with endogenous anterior uveitis.
[0346] Corticosteroid eye drops have been in use since the 1950s
for controlling ocular inflammation. Extensive clinical experience
attests to the efficacy of these compounds for treating anterior
segment inflammation (Gaudio 2004). Controlling inflammation is one
of the key objectives following ocular surgery. Difluprednate is a
potent corticosteroid that is regularly used by physicians
following ocular surgery in the US standard of care. A
glucocorticoid (GC) receptor-binding test was performed to evaluate
GC receptor-binding activity (GCRBA) of glucocorticoids.
Difluprednate's active metabolite DFB had the highest affinity for
the GR with the lowest inhibition constant (K.sub.j) when compared
with prednisolone, betamethasone, fluorometholone, and
dexamethasone (Table 21) (Tajika 2011b). The greater binding
affinity may be attributed to the unique molecular structure of
difluprednate. Difluprednate is a derivative of prednisolone, but
differs substantially due to structural modifications. The addition
of two fluorines and a C-17 butyrate directly increase the affinity
of difluprednate for the GR (Donnenfeld 2011).
TABLE-US-00024 TABLE 21 K.sub.i Values of Difluprednate, Its
Metabolite, and Various Glucocorticoids Compound K.sub.i Value
(mol/L) Difluprednate (DFBA) 7.8 .times. 10.sup.-10 .+-. 3.6
.times. 10.sup.-11 Desacetyl Difluprednate (DFB) 6.1 .times.
10.sup.-11 .+-. 1.2 .times. 10.sup.-11 Prednisolone 3.4 .times.
10.sup.-9 .+-. 7.3 .times. 10.sup.-10 Betamethasone 1.7 .times.
10.sup.-9 .+-. 3.2 .times. 10.sup.-10 Dexamethasone 1.9 .times.
10.sup.-9 .+-. 2.3 .times. 10.sup.-10
[0347] Studies of topical difluprednate in rabbits show that it is
effective in models of post-operative inflammation when applied 4
times daily (QID; DUREZOL.RTM. NDA 22-212). Difluprednate has been
studied in humans, and the efficacy and safety of topical ocular
administration of DUREZOL.RTM. is established (Korenfeld 2009,
Foster 2010).
[0348] Proposed Manufacturing Protocol of ENV905
[0349] Based upon the data contained in the present disclosure, the
inventors anticipate large scale production of the ENV905 product.
Both PEG 3,350 and PEG 100,000 will be manufactured in a current
Good Manufacturing Practices (cGMP)-compliant process and comply
with current National Formulary (NT) compendia specifications (USP
37-NF 32 Monographs for Polyethylene Glycol and Polyethylene
Oxide). The ENV905 implant will be compounded and packaged in a low
bioburden environment and may be terminally sterilized by gamma
irradiation.
[0350] Description of Manufacturing Process and Process Controls
for ENV905
[0351] Manufacture of ENV905 (difluprednate) ophthalmic implant is
a well-controlled, multi-step process used to produce implants
composed of micronized difluprednate contained within a
biocompatible PEG drug delivery system.
[0352] The process begins with the fabrication and sterilization of
the mold template that will be used to form the final implant
geometry. The mold is formed by patterning a series of cavities
into an ultraviolet (UV) curable polymer material. The resulting
mold is a flexible sheet with an array of cavities of uniform size
and shape. The mold sheet is then sterilized by gamma irradiation
at Steris Isomedix, Inc. prior to use. A polyethylene terephthalate
(PET) backing sheet used in the molding process is also sterilized
by gamma irradiation at Steris Isomedix.
[0353] Micronized difluprednate is first compounded with the two
PEGs at a specified ratio to create a homogeneous blend. The blend
is then heated above the melting point of the PEGs to allow for the
PEGs to freely flow creating a homogenous solid dispersion with the
micronized difluprednate. The ENV905 (difluprednate) ophthalmic
implant is then formed by thermally molding the resulting
difluprednate/PEG blend into the desired geometrical shape using
the pre-sterilized mold and backing sheet. This manufacturing step
is performed in an International Standard for Organization (ISO) 5
environment. The final implant is prism-shaped with a size defined
by the mold sheet cavities. The formed implants are then manually
transferred in an ISO 5 environment into a pre-sterilized container
closure. The packaged implants will then be terminally sterilized
via gamma irradiation.
[0354] Implant Mold Fabrication
[0355] The final shape of the ENV905 (difluprednate) ophthalmic
implant is defined by a molding process which uses a polymer mold
template which consists of a polymer coating (referred to as
SAE-04) that is applied to a backing sheet of PET. The SAE-04
material is a UV-curable silicone that can be patterned to form
mold cavities in the desired shape and size of the implant.
[0356] The mold-making process begins with a master template
fabricated on a silicon wafer through a process known in the
microelectronics industry as photolithography. This master template
consists of an array of uniformly sized and shaped features having
nominally the same size and geometry as the final implant.
[0357] Through a series of replication steps referred to as mold
making, the master template is then used to create a polymer mold
template. First, the PET backing sheet is coated with a thin layer
of an acrylate polymer to serve as an adhesive promoting tie-layer.
This acrylate layer ensures that the SAE-04 mold adheres to the PET
backing layer. Liquid SAE-04 monomer is premixed with a
photo-initiator referred to as TMP
(diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide) to drive the
polymerization reaction during mold making. A small volume of
SAE-04 solution is dispensed onto the PET backing sheet to form a
film, and is covered with the master template. The sample is then
exposed to UV light (.lamda..sub.avg=265 nm) for 60 to 120 seconds
to polymerize the mold film while in contact with the pattern on
the master template. This creates a series of rectangular cavities
in the mold film. The solidified mold and PET backing layer are
then peeled off of the master template to create a free-standing
mold.
[0358] The mold is then inspected visually for macroscopic defects
and mold cavity dimensions are verified using optical profilometry
to measure the cavity depth. The mold is then double-bagged in
self-sealing sterilization pouches and shipped to an external
vendor for sterilization using gamma irradiation.
[0359] Preparation of Difluprednate/PEGs Blend for ENV905
[0360] All manufacturing procedures are performed at ambient
temperature unless otherwise specified. Micronized difluprednate,
PEG 3,350, and PEG 100,000 are all received as dry powders. The
individual components are weighed and mixed at a given ratio. They
are first thoroughly mixed as a dry powder blend by mechanical
agitation. To ensure a homogenous blend, the dry powder blend is
then heated above the melting points of the polymers. The polymers
can then freely flow and form a homogeneous solid dispersion with
the micronized difluprednate. The homogenous difluprednate/PEG
blend solidifies as it cools down back to room temperature.
[0361] Preparation of Molded Implant
[0362] Individual implants are formed by heating the
difluprednate/PEG blend and allowing it to flow into the cavities
of the mold. Table 24 includes proposed processing parameters. This
process takes place in two BSC hoods (ISO 5 environment). The
difluprednate/PEG blend is placed on the PET sheet and placed on a
hot plate for 120-180 seconds. Once heated, the blend is covered
with the Fluorocur.RTM. (FCR) mold sheet. Light pressure is applied
using a hand roller to laminate the two sheets together. The
mold/blend laminate is then passed through a commercially available
thermal laminator at a specified temperature, speed, and pressure.
Under these conditions the difluprednate/PEG blend is able to flow
into the mold cavities, filling the cavities, and assuming the
shape of the mold cavities. The laminate containing the
difluprednate/PEG blend in the mold cavities is then allowed to
cool back down to room temperature. The difluprednate/PEG blend
then solidifies forming individual, discrete implants. The mold can
then be removed, leaving a two-dimensional array of discrete
implants on the PET film.
TABLE-US-00025 TABLE 24 ENV905 Implant Fabrication Conditions
Process Parameter Proposed Range Hot Plate Temp (.degree. C.)
120-160 Hot Plate Time (sec) 120-180 Laminator Temp (.degree. F.)
260-320 Laminator Speed (ft/min) 0.1-1.sup. Laminator Pressure
(psi) 40-80 Number of Lamination Passes 4-8 Cooling time (min:sec)
NLT 3:00
[0363] Implant Packaging
[0364] It is envisioned that in an embodiment the packaging for the
ENV905 implants will be a blister pack comprised of a thermoformed
film with each well containing individual dosage units, foil or
foil laminate lidding, and a pressure-seal coating. Individual
implants will be manually removed from the PET backing sheet using
stainless steel tweezers. Alternatively, sterile vials may be used.
Each implant will be visually inspected for macroscopic defects
before placing it in its final packaging. It is envisioned that the
ENV905 implants will be preloaded into an ENV905 implant
Applicator, with the needle hub assembly of the Applicator
functioning as a container closure for the implants.
[0365] Sterility Assurance
[0366] Terminal moist heat sterilization is not a viable method due
to the fact that ENV905 is a solid dosage form designed to
disintegrate in aqueous environments. Therefore, studies to
evaluate gamma irradiation were conducted on early ENV905
formulations to determine if ionizing radiation was a viable option
for a terminally sterilized drug product. ENV905 implants were
exposed to gamma irradiation with a dose of 46 kGy per ISO
11137-2:2012 (Sterilization of Health Care
Products--Radiation--Part 2: Establishing the Sterilization Dose).
The implant formulations used for these studies consisted of a
blend of difluprednate and PEGS. The compositions and sizes of the
implant formulations used in the study are provided in Table 25
below.
TABLE-US-00026 TABLE 25 Difluprednate Implant Formulations
(ENV-1I-115-8) Mean Implant Difluprednate PEG Ratio Formula-
Dimensions Content (.mu.g) SD % (PEG 3,350/ tion ID (.mu.m) (n =
10) (.mu.g) RSD PEG 100,000) ENV-1I- 225 .times. 225 .times. 97.2
2.6 2.7 q.s. ad 115-8-3 4,000 11%/89% ENV-1I- 225 .times. 225
.times. 74.1 1.3 1.7 q.s. ad 115-8-5 2,925 11%/89% ENV-1I- 225
.times. 225 .times. 38.9 1.0 2.5 q.s. ad 115-8-7 2,925 11%/89%
[0367] Implants were individually packaged in HPLC vials with air
headspace and polytetrafluoroethylene (PTFE)-lined screw caps. Ten
individual implants (n=10) were tested for difluprednate assay. The
results are summarized in Table 26.
TABLE-US-00027 TABLE 26 Impact of Gamma Irradiation (46 kGy) on
Difluprednate Assay on Difluprednate/PEG Implant Formulations
Radia- Mean Difluprednate Diflu- tion Content prednate Degrada-
Formula- Dose (.mu.g/implant) SD Assay tion tion (kGy) (n = 10
implants) (.mu.g) (% Area) (% Area) Neat API None -- -- 97.98 -- 46
-- -- 97.13 0.85 Implant None 97.2 2.6 97.19 -- ENV-1I- 46 101.2
5.5 96.80 0.39 115-8-3 Implant None 74.1 1.3 97.54 -- ENV-1I- 46
73.1 5.1 97.01 0.53 115-8-5 Implant None 38.9 1.0 97.92 -- ENV-1I-
46 40.1 1.4 97.31 0.61 115-8-7
[0368] Gamma irradiation under standard sterilization conditions
(46 kGy) resulted in 0.39% to 0.61% degradation of difluprednate in
the drug product, and 0.85% degradation of neat difluprednate.
[0369] The effect of gamma irradiation disintegration time and
difluprednate content in media upon full disintegration of the
implants was also evaluated. Implants were individually packaged in
HPLC vials with air headspace and PTFE-lined screw caps. Five (n=5)
implants were tested for difluprednate assay in the media after a
prescribed time of 5 minutes to achieve full disintegration. The
results are summarized in Table 27.
TABLE-US-00028 TABLE 27 Impact of Gamma Sterilization on In Vitro
Difluprednate Disintegration Test. Disintegration Medium: 0.01M
Phosphate Buffered Saline, 1% SDS; Temperature = 20.degree. C. Mean
Difluprednate Content Measured in Media upon Full Implant
Disintegration Radiation Dose (.mu.g/implant) SD Formulation (kGy)
(n = 5 implants) (.mu.g) ENV-1I-115-8-3 None 103.3 4.3 46 104.4 5.0
ENV-1I-115-8-5 None 73.2 3.3 46 72.4 4.8 ENV-1I-115-8-7 None 40.7
1.1 46 40.6 0.8
[0370] Gamma irradiation did not statistically impact the amount of
difluprednate recovered in the media after full disintegration.
Furthermore, gamma irradiation did not have an impact on the time
required to achieve full disintegration in media (t.ltoreq.5
minutes)
[0371] Based on these preliminary sterilization studies described
above, the inventors contemplate that in some embodiments they will
terminally sterilize ENV905 drug product using gamma irradiation. A
sterility assurance level of 10.sup.-6 or better will be
demonstrated for the developed cycle.
[0372] Raw Materials and Proposed Excipient Specifications for
ENV905
[0373] The raw materials and proposed specifications for the PEG
excipients used to manufacture ENV905 (difluprednate) implants are
summarized in Tables 28-31 below. The PEG excipients will be in
conformance with NF compendia' specifications.
TABLE-US-00029 TABLE 28 List of Raw Materials for ENV905 Material
Name (product number) Purpose Difluprednate Active Poly(ethylene
glycol) Diluent 3,350 Poly(ethylene glycol) Diluent/Binder
100,000
TABLE-US-00030 TABLE 29 List of Raw Materials for Mold Fabrication
Material Name (product number) Purpose Polyethylene terephthalate
(PET), Substrate Backing Layer 5 mil (Melinex 453) SR9012
(tri-functional acrylate ester) Mold Tie Layer Component DPT;
(Diphenyl(2,4,6- Mold Tie Layer trimethylbenzoyl) phosphine oxide/
Component 2-hydroxy-2-methylpropiophenone) Fluorocur-SAE-04; FCR
Mold Resin Acrylated Polysiloxanes; Siloxanes Component and
Silicones, di-Me, hydrogen terminated, reaction products with
acrylic acid and 2-ethyl-2-[(2- propenyloxy)methyl]-1,3-propanol
TMP; Diphenyl(2,4,6- FCR Mold Resin trimethylbenzoyl)phosphine
oxide Component (CAS# 75980-60-8)
TABLE-US-00031 TABLE 30 Proposed Specifications for Poly(ethylene
glycol); 3,350 MW Proposed Test Specification Method Description
Physical Appearance White to off - white Visual powder Average
Molecular 90.0 to 110.0% of Titrimetric (NF Weight nominal value
Monograph) Residue on Ignition NMT 0.1% USP<281> Heavy Metals
NMT 5 ppm USP<231> Free Ethylene Dioxide NMT 10 .mu.g/g
Headspace GC - FID (NF Monograph) Free 1,4-Dioxane NMT 10 .mu.g/g
Headspace GC - FID (NF Monograph) pH (5.0 g of Poly- 4.5 to 7.5
USP<791> ethylene Glycol in 100 mL of carbon dioxide-free
water) Completeness and Color Colorless and Clear NF Monograph of
Solution Viscosity 9 to 15 cPs (25% w/w, Viscometry H.sub.2O at
25.degree. C.) Microbial Limits Total microbial count .ltoreq.2000
CFU/g USP<61> Yeasts and molds .ltoreq.200 CFU/g Tests for
specified Absence of S. aureus, USP<62> microorganisms E.
coli, Salmonella, P. aeruginosa
TABLE-US-00032 TABLE 31 Proposed Specifications for Poly(ethylene
glycol); 100,000 MW Test Proposed Specification Method Description
Physical Appearance White to off - white Visual (NF powder
Monograph) Infrared Absorption Spectrum consistent with
USP<197K> reference standard Viscosity 12 to 50 cPs (c = 5%,
Viscometry H.sub.2O, at 25.degree. C.) Heavy Metals NMT 10 ppm
USP<231> Method II Silicon Dioxide NMT 3% NF Monograph
Residue on Ignition Non-Silicon Dioxide NMT 2% NF Monograph Residue
on Ignition Free Ethylene Dioxide NMT 0.001% Headspace GC - FID (NF
Monograph) Loss On Drying NMT 1.0% USP<731> Microbial Limits
Total microbial count .ltoreq.2000 CFU/g USP<61> Yeasts and
molds .ltoreq.200 CFU/g Tests for specified Absence of S. aureus,
USP<62> microorganisms E. coli, Salmonella, P. aeruginosa
[0374] Nonclinical Pharmacology of ENV905
[0375] Multiple pharmacology studies of various formulations of
ENV905 have been conducted in albino rabbit models of ocular
post-operative inflammation.
[0376] Animal models included corneal incision, lens
phacoemulsification, and anterior chamber paracentesis. The effect
of ENV905, placebo implant, or positive control DUREZOL.RTM. on
induced ocular inflammation was assessed over approximately 1
month, and the results are discussed in this section.
[0377] The anti-inflammatory effects of topical difluprednate have
been established, and the kinetics of the deacetylation of
difluprednate to its active metabolite desacetyl difluprednate
(DFB) in vivo are known (Tajika 2011a, Tajika 2011b).
[0378] However, the pharmacology of extended release SCJ or IC
delivery of difluprednate has not been studied, although delivery
of other corticosteroids to these compartments demonstrates a
reduction in ocular inflammation (Croasdale 1999, Deileman 2011,
Koval 2014).
[0379] Nonclinical Pharmacology of ENV905 General Experimental
Protocol
[0380] Four non-Good Laboratory Practices (GLP) efficacy and
tolerability studies of ENV905 formulations have been completed in
NZW rabbits (Table 32).
[0381] On Day 1, animals received either a bilateral corneal
incision, which mimics the incision encountered during cataract
surgery (studies ENV905-PRE-003, ENV905-PRE-006, and
ENV905-PRE-008), or lens phacoemulsification (study
ENV905-PRE-004), and were given a single bilateral administration
of ENV905 or placebo implant concurrent with the surgical
procedure.
[0382] DUREZOL.RTM. administered topically 4 times per day starting
at the time of surgery served as the positive control. The dosing
paradigm for DUREZOL.RTM. was one drop per eye, four times daily
for the duration of the study. For a negative control, the surgery
was conducted and a placebo implant (difluprednate-free) was
inserted.
[0383] Animals were observed for general tolerability endpoints,
and received ophthalmic exams at regular intervals during the
study. As these models generally induce ocular inflammation for a
limited amount of time, additional inflammation induction in the
form of paracentesis (removal of an aliquot of aqueous humor) were
conducted at approximately weekly intervals to enable assessment of
the duration of anti-inflammatory effect of ENV905.
[0384] Specifically, for the ENV905-PRE-006 study, anterior chamber
paracentesis was conducted on Days 9, 15, and 22 to induce ocular
inflammation. Eyes were examined on Days -2 (baseline), 3, 4, 9,
10, 11, 15, 16, 17, 22, 23, and 24 by a board certified veterinary
ophthalmologist and were graded using the Hackett and McDonald
Ophthalmic Exam Scoring System. See, Hackett, R D and McDonald, T
O. Ophthalmic Toxicology and Assessing Ocular Irritation.
Dermatoxicology, 5.sup.th edition. Ed. F N Marzulli and H I
Maibach. Washington, D.C.: Hemisphere Publishing Corporation. 1996;
299-305 and 557-566.
[0385] Multiple formulations of ENV905 have been assessed in the
pharmacology studies, and both routes of administration,
subconjunctival and intracameral, were employed (Tables 33-35).
[0386] Specifically, ENV905 implants were assessed for effect on
induced ocular inflammation in NZW rabbits following a single SCJ
or IC dose administration on Day 1 (Table 32 and 33). Custom
implant applicators with 21 G to 27 G needles were used to
administer the implants. Placebo implant formulations were used as
negative controls, and DUREZOL.RTM. dosed QID throughout the study
served as the positive control group.
[0387] Ocular inflammation was induced by one of two methods: a 2.7
mm clear corneal incision approximately 1 mm from the limbus; a
phacoemulsification procedure involving a surgical 2.7 mm clear
corneal incision at the superior limbus, a central curvilinear
capsularexis, and removal of the lens cortex and nucleus by
phacoemulsification and aspiration. Additionally, as the induced
ocular inflammation was relatively short lived and in order to
assess effect on inflammation at later time points, animals also
received anterior chamber paracentesis at predetermined time
points, involving a 30 G needle placed through the limbus and
removal of aqueous humor, at pre-determined time points during each
study. General tolerability endpoints included body weights and
daily clinical observations. A board-certified veterinary
ophthalmologist performed ophthalmic exams and McDonald-Shadduck
scoring to assess ocular inflammation.
TABLE-US-00033 TABLE 32 Summary of Completed Pharmacology Studies
of ENV905 Dura- No. of tion Animals/ Regulatory Study Model (Days)
Species Group Status Number Corneal 24 NZW 2-4 Non-GLP ENV905-
Incision and Rabbit PRE-003 Paracentesis 25 NZW 2-4 Non-GLP ENV905-
Rabbit PRE-006 31 NZW 4 Non-GLP ENV905- Rabbit PRE-008 Phaco- 28
NZW 2-4 Non-GLP ENV905- emulsification Rabbit PRE-004 and
Paracentesis
TABLE-US-00034 TABLE 33 ENV905 Formulations Tested in Pharmacology
Studies in New Zealand White Rabbits ENV905 Implant Number of Total
Dose (.mu.g Route of Formulation ID PEG Ratio Dimensions (.mu.m)
Implants/Eye difluprednate/Eye) Administration Study Number
ENV-1I-53-32-1 PEG 35K/PEG 100K (70/30) 300 .times. 300 .times.
6,000 2 0 SCJ ENV905-PRE-003 ENV-1I-53-23-5 PEG 35K/PEG 100K
(70/30) 225 .times. 225 .times. 4,000 2 210 SCJ ENV905-PRE-003
ENV-1I-53-28-1 PEG 35K/PEG 100K (70/30) 300 .times. 300 .times.
6,000 2 432 SCJ ENV905-PRE-003 ENV-1I-53-28-2 PEG 35K/PEG 100K
(70/30) 300 .times. 300 .times. 6,000 3 1,152 SCJ ENV905-PRE-003
ENV-1I-53-28-3 PEG 1,000K (100) 300 .times. 300 .times. 6,000 3
1,158 SCJ ENV905-PRE-003 ENV-1I-115-3 PEG 35K/PEG 100K (70/30) 225
.times. 225 .times. 4,000 2 0 SCJ ENV905-PRE-004 ENV-1I-115-4 PEG
35K/PEG 100K (70/30) 300 .times. 300 .times. 6,000 2 0 SCJ
ENV905-PRE-004 ENV-1I-115-1 PEG 35K/PEG 100K (70/30) 225 .times.
225 .times. 4,000 2 202 SCJ or IC ENV905-PRE-004 ENV-1I-115-2 PEG
35K/PEG 100K (70/30) 300 .times. 300 .times. 6,000 1 or 3 413 or
1,239 SCJ ENV905-PRE-004 ENV-1I-115-8-10 PEG 100K/PEG 3,350 (89/11)
225 .times. 225 .times. 2,925 1 0 IC ENV905-PRE-006 ENV-1I-115-23-1
PEG 100K/PEG 3,350 (89/11) 300 .times. 300 .times. 6,000 1 0 SCJ
ENV905-PRE-006 ENV-1I-115-8-3 PEG 100K/PEG 3,350 (89/11) 225
.times. 225 .times. 4,000 2 204 IC ENV905-PRE-006 ENV-1I-115-8-5
PEG 100K/PEG 3,350 (89/11) 225 .times. 225 .times. 2,925 1 74 IC
ENV905-PRE-006 ENV-1I-115-8-7 PEG 100K/PEG 3,350 (89/11) 225
.times. 225 .times. 2,925 1 40 IC ENV905-PRE-006 ENV-1I-115-16-1
PEG 100K/PEG 3,350 (89/11) 300 .times. 300 .times. 6,000 1 390 SCJ
ENV905-PRE-006 ENV-1I-115-37-1 PEG 100K/PEG 3,350 (89/11) 225
.times. 225 .times. 2,925 1 0 IC ENV905-PRE-008 ENV905-2I-178-20-4
PEG 100K/PEG 3,350 (89/11) 225 .times. 225 .times. 2,925 1 10 IC
ENV905-PRE-008 ENV905-2I-178-20-1 PEG 100K/PEG 3,350 (89/11) 225
.times. 225 .times. 2,925 1 20 IC ENV905-PRE-008 ENV905-2I-0178-25
PEG 100K/PEG 3,350 (89/11) 225 .times. 225 .times. 2,925 1 44 IC
ENV905-PRE-008
TABLE-US-00035 TABLE 34 Polymer Matrix/Therapeutic Agent Blend
Ratio For ENV905-PRE-006 and ENV905-PRE-008 Implants Polymer Matrix
Target, % Therapeutic PEG PEG Agent Study No. ID 100K 3350 Target,
% ENV905- ENV-1I-115-8-10 89.0 11.0 0.0 PRE-006 ENV-1I-115-23-1
89.0 11.0 0.0 ENV-1I-115-8-3 44.5 5.5 50.0 ENV-1I-115-8-5 44.5 5.5
50.0 ENV-1I-115-8-7 66.75 8.25 25.0 ENV-1I-115-16-1 44.5 5.5 50.0
ENV905- ENV-1I-115-37-1 89.0 11.0 0 PRE-008 ENV905-2I-178- 89.0
11.0 8 20-4 ENV905-2I-178- 89.0 11.0 14 20-1 ENV905-2I-0178- 89.0
11.0 26.4 25
TABLE-US-00036 TABLE 35 Implants Administered in ENV905-PRE-006 and
ENV905-PRE-008 No. Therapeutic Agent Therapeutic Therapeutic No.
Implants Eyes Content/Implant Agent Dose/Eye Agent Dose/ Study No.
ID Dosed/Eye Dosed (.mu.g) (.mu.g) Animal (.mu.g) ENV905-PRE-006
Positive Control 0 8 0 0 0 ENV-1I-115-8-10 1 4 0 0 0
ENV-1I-115-23-1 1 4 0 0 0 ENV-1I-115-8-3 2 8 102.2 204.4 408.8
ENV-1I-115-8-5 1 8 74.3 74.3 148.6 ENV-1I-115-8-7 1 8 40.2 40.2
80.4 ENV-1I-115-16-1 1 8 390.3 390.3 780.6 ENV905-PRE-008
ENV-1I-115-37-1 1 8 0 0 0 ENV905-2I-178-20-4 1 8 10 10 20
ENV905-2I-178-20-1 1 8 20 20 40 ENV905-2I-0178-25 1 8 44 44 88
[0388] Nonclinical Pharmacology of ENV905 Results
[0389] Dose administration via the SCJ or IC route was conducted
successfully, and there were no adverse findings related to the
dosing procedure noted in any study. Ocular inflammation was
successfully induced via corneal incision or phacoemulsification,
as observed by ophthalmic exam, and clinical findings related to
the surgical procedure included conjunctival hyperemia and
chemosis, iritis, and aqueous and cellular flare; these findings
generally decreased in severity by Day 7. Anterior chamber
paracentesis was conducted at the predetermined time points, and
induced findings similar in nature, but diminished in severity,
compared with those observed following the surgical procedures.
Positive control DUREZOL.RTM. dampened the inflammatory response
following surgery or paracentesis as expected.
[0390] SCJ ENV905 Results
[0391] SCJ ENV905, dosed at approximately 400 .mu.g of
difluprednate per eye, reduced inflammation following corneal
incision at a level similar or superior to that observed with QID
DUREZOL.RTM. (.about.100 .mu.g difluprednate per day, assumes 50
.mu.L/drop) (FIG. 9 and FIG. 10).
[0392] Following the more invasive lens phacoemulsification
surgery, SCJ ENV905 at .about.400 .mu.g difluprednate per eye did
not reduce inflammation at 24 and 48 hours post-surgery when
compared with QID DUREZOL.RTM., but was equivalent in efficacy to
DUREZOL.RTM. at all other time points (FIG. 11).
[0393] Note that DUREZOL.RTM. dosing was initiated at the time of
surgery in all studies, contrary to the package label instructions
which recommend beginning DUREZOL.RTM. administration 24 hours
post-surgery. Additionally, sufficient difluprednate following
subconjunctival administration was present following a single
administration on Day 1 to enable reduction of inflammation via
paracentesis at each subsequent induction time point through Day
24/28 (FIGS. 9-11).
[0394] IC ENV905 Results
[0395] IC ENV905, dosed as a single administration of either 10,
20, 40 or 44 .mu.g of difluprednate via one implant per eye,
decreased the level of induced inflammation following corneal
incision in a manner which was similar or superior to that observed
with QID DUREZOL.RTM. (.about.100 .mu.g difluprednate per day,
assumes 50 .mu.L/drop) at most time points throughout the 24-day or
31-day study period (FIG. 12 and FIG. 20). IC ENV905, dosed as a
single administration of .about.200 .mu.g of difluprednate via two
implants per eye, was equivalent to QID DUREZOL.RTM. at the early
time points following phacoemulsification surgery, and was
generally equivalent or superior to DUREZOL.RTM. at the later time
points (FIG. 13).
[0396] FIG. 14 illustrates the Total Hackett-McDonald Ophthalmic
Exam Score (Mean.+-.SD) for all ENV905 intracameral implants tested
in the ENV905-PRE-006 study.
[0397] FIG. 15 illustrates the Total Hackett-McDonald Ophthalmic
Exam Score (Mean.+-.SD) for all ENV905 intracameral and
subconjunctival implants tested in the ENV905-PRE-006 study.
[0398] FIG. 20 illustrates the Total Hackett-McDonald Ophthalmic
Exam Score (Mean.+-.SEM) for all ENV905 intracameral implants
tested in the ENV905-PRE-008 study.
[0399] ENV905 In Vivo Animal Model Test Conclusions
[0400] Data from the aforementioned non-G-LP pharmacology studies
of various formulations of ENV905 indicate that, whether
administered via the SCJ or IC routes, ENV905 decreases ocular
inflammation following ocular surgery in the rabbit, at dose levels
ranging from 40 to 400 .mu.g of difluprednate per eye. A similar
effect is expected in humans.
[0401] No adverse effects were noted in any study, and the implants
were well tolerated in this species.
[0402] A significant dose sparing effect was observed with both SCJ
and IC ENV905, with excellent anti-inflammatory effects observed at
doses of difluprednate that were significantly less than the dose
of difluprednate via topical DUREZOL.RTM..
[0403] Pharmacokinetics of ENV905
[0404] Pharmacokinetics (often abbreviated PK) is the
pharmacological study of how an administered drug is absorbed,
distributed, metabolized, and eliminated by the body. See, Rowland
and Tozer, "Clinical Pharmacokinetics and Pharmacodynamics:
Concepts and Applications," 4.sup.th Ed., 2011, Lippincott Williams
& Wilkins publishers, which is incorporated herein by reference
in its entirety for all purposes.
[0405] Systemic and ocular PK was assessed as part of the ENV905
pharmacology studies discussed above and two ocular pharmacokinetic
studies.
[0406] Matrixes included aqueous humor, cornea, trabecular
meshwork, iris/ciliary body, bulbar conjunctiva, subconjunctival
dose site (SCJ only), retina, and plasma. Ocular matrixes were
analyzed for both the parent molecule, difluprednate (DFBA), as
well as the active metabolite, desacetyl difluprednate (DFB).
Plasma was analyzed for DFB only, as the conversion to the active
metabolite occurs within the ocular tissue prior to systemic
absorption. Systemic exposure to DFB was minimal and was generally
below the limit of quantitation by Day 7. Concentrations of DFBA
and DFB in ocular tissue were dose dependent as well as dependent
on the route of administration.
[0407] Bioanalytical Methods
[0408] Bioanalytical methods for difluprednate (DFBA), the active
metabolite (DFB), and their internal standard DFB-d.sub.6 were
developed and qualified in albino rabbit matrixes by Intertek
Laboratories (San Diego, Calif.) using liquid-liquid extraction and
high performance liquid chromatography and tandem mass spectrometry
(LC-MS/MS). Methods in rabbit aqueous humor, cornea, trabecular
meshwork, iris/ciliary body, bulbar conjunctiva, subconjunctival
dose site (SCJ only), retina, and plasma (DFB only) were qualified
for range of reliable response, selectivity, carryover assessment,
and precision and accuracy.
TABLE-US-00037 TABLE 36 ENV905 Formulations Tested for
Pharmacokinetics in Tolerability, Pharmacology, and
Pharmacokinetics Studies in New Zealand White Rabbits. ENV905
Number of Total Dose (.mu.g Formulation Implant Implants/
difluprednate/ Route of Matrices ID PEG Ratio Dimensions (.mu.m)
Eye Eye) Administration Study Number Analyzed ENV-1I-115-3 PEG
35K/PEG 100K 225 .times. 225 .times. 4,000 2 0 SCJ ENV905-PRE-
Aqueous Humor, (70/30) 004 Conjunctiva ENV-1I-115-4 PEG 35K/PEG
100K 300 .times. 300 .times. 6,000 2 0 SCJ ENV905-PRE- Aqueous
Humor, (70/30) 004 Conjunctiva ENV-1I-115-1 PEG 35K/PEG 100K 225
.times. 225 .times. 4,000 2 202 SCJ or IC ENV905-PRE- Aqueous
Humor, (70/30) 004 Conjunctiva ENV-1I-115-2 PEG 35K/PEG 100K 300
.times. 300 .times. 6,000 1 or 3 413 or 1,239 SCJ ENV905-PRE-
Aqueous Humor, (70/30) 004 Conjunctiva ENV-1I-115-4 PEG 35K/PEG
100K 300 .times. 300 .times. 6,000 2 0 SCJ ENV905-PRE- Plasma
(Placebo) (70/30) 005 ENV-1I-53-28-1.sup.1 PEG 35K/PEG 100K 300
.times. 300 .times. 6,000 2 432 SCJ ENV905-PRE- Plasma (70/30) 005
ENV-1I-115-2 PEG 35K/PEG 100K 300 .times. 300 .times. 6,000 2 826
SCJ ENV905-PRE- Plasma (70/30) 005 ENV-1I-115-8-10 PEG 100K/PEG
3,350 225 .times. 225 .times. 2,925 1 0 IC ENV905-PRE- Aqueous
Humor (89/11) 006 ENV-1I-115-23-1 PEG 100K/PEG 3,350 300 .times.
300 .times. 6,000 1 0 SCJ ENV905-PRE- Aqueous Humor (89/11) 006
ENV-1I-115-8-3 PEG 100K/PEG 3,350 225 .times. 225 .times. 4,000 2
204 IC ENV905-PRE- Aqueous Humor (89/11) 006 ENV-1I-115-8-5 PEG
100K/PEG 3,350 225 .times. 225 .times. 2,925 1 74 IC ENV905-PRE-
Aqueous Humor (89/11) 006 ENV-1I-115-8-7 PEG 100K/PEG 3,350 225
.times. 225 .times. 2,925 1 40 IC ENV905-PRE- Aqueous Humor (89/11)
006 ENV-1I-115-16-1 PEG 100K/PEG 3,350 300 .times. 300 .times.
6,000 1 390 SCJ ENV905-PRE- Aqueous Humor (89/11) 006 ENV905-1 PEG
100K/PEG 3,350 225 .times. 225 .times. 2,925 3 121.5 IC
ENV905-ADME- Plasma Aqueous (89/11) 001 Humor, Cornea/TM,
Iris/Ciliary Body, Conjunctiva, Retina ENV905-2 PEG 100K/PEG 3,350
300 .times. 300 .times. 6,000 3 1207.5 SCJ ENV905-ADME- Plasma
Aqueous (89/11) 001 Humor, Cornea/TM, Iris/Ciliary Body,
Conjunctiva, Retina ENV905-1 PEG 100K/PEG 3,350 225 .times. 225
.times. 2,925 1, 2, or 3 42.8, 85.6, or IC ENV905-ADME- Plasma
Aqueous (89/11) 128.4 002 Humor, Cornea, Trabecular Meshwork,
Iris/Ciliary Body, Conjunctiva, Retina ENV905-1 PEG 100K/PEG 3,350
225 .times. 225 .times. 2,925 1, 2, or 3 44, 88, or 132 IC
ENV905-TOX- Plasma (89/11) 001
[0409] Plasma Concentration Data from Tolerability Study
ENV905-PRE-005
[0410] Animals received a single, bilateral administration of SCJ
ENV905 (432 or 826 .mu.g difluprednate per eye) or placebo
implant.
[0411] There was no detectable DFB in plasma from placebo animals
(LLOQ 0.05 ng/mL).
[0412] Following subconjunctival administration of ENV905, DFB in
plasma peaked on Day 2 (24 hours post-dose), with concentrations of
0.68 and 0.72 ng/mL for 432 and 826 .mu.g difluprednate per eye
(864 and 1,652 .mu.g difluprednate per animal), respectively. See,
Table 37.
[0413] Systemic exposure to DFB decreased rapidly through Days 4
and 7, and was undetectable at later time points. In comparison to
a previously published study, DFB in plasma following topical
DUREZOL.RTM. administration was approximately 10 ng/mL at 30
minutes post-dose (Tajika 2011a).
[0414] These data demonstrate decreased systemic exposure to DFB
following ENV905 administration when compared with QID
DUREZOL.RTM..
TABLE-US-00038 TABLE 37 Concentration of DFB in Rabbit Plasma
Following Subconjunctival ENV905 Concentration Formulation Study of
DFB Study Number (.mu.g DFBA) Day Parameter (ng/mL) ENV905-PRE-
ENV1I-53-28-1 2 Mean 0.678 005 (432) SD 0.238 4 Mean 0.116 SD
0.0278 7 Mean BLQ SD NA 14 Mean BLQ SD NA 29 Mean BLQ SD NA
ENV905-PRE- ENV1I-115-2 2 Mean 0.720 005 (826) SD 0.232 4 Mean
0.206 SD 0.0872 7 Mean 0.0415 SD 0.0542 14 Mean BLQ SD NA 29 Mean
BLQ SD NA
[0415] Aqueous Humor Concentration Data from Pharmacology
Studies
[0416] Aqueous humor (AH) was obtained in the pharmacology studies
described above, as part of the inflammation induction method of
anterior chamber paracentesis.
[0417] An approximately 100 .mu.L sample was obtained by the
veterinary ophthalmologist using a 30 G needle inserted at the
litribus. Samples were analyzed for DFBA and DFB in studies
ENV905-PRE-004 and ENV905-PRE-006. Sampling days varied slightly
across studies due to ophthalmologist availability.
[0418] In ENV905-PRE-004, animals received a single bilateral
administration of ENV905, and AR was sampled on Days 9, 21, and 28.
SCJ ENV905 doses were 413 or 1,239 .mu.g of difluprednate per eye,
and the IC dose was 202 .mu.g difluprednate per eye. There was no
detectable DFBA or DFB in AH obtained from placebo animals.
Following a dose of 413 .mu.g of difluprednate per eye, DFB was
detectable on Day 9 and below the lower limit of quantification
(LLOQ) at later time points. Following the 1,239 .mu.g
difluprednate per eye dose, DFB was detectable at all time points
through Day 28. See, Tables 38-39.
[0419] In ENV905-PRE-006, animals received a single bilateral
administration of ENV905, and AH was sampled on Days 9, 15, and 24.
The SCJ dose was 390 .mu.g difluprednate per eye, and IC doses were
40 and 74 .mu.g difluprednate per eye. There was no detectable DFBA
or DFB in AH obtained from placebo animals. SCJ ENV905 demonstrated
no detectable DFB on Day 9, but was detectable at low
concentrations on Days 15 and 24. IC ENV905 had very few samples
with detectable DFB concentrations, potentially due to sampling
only on Day 9 or later, while robust efficacy was seen in all
animals throughout following this route of dose administration.
See, Tables 38-39.
TABLE-US-00039 TABLE 38 Concentration of DFBA and DFB in Rabbit
Aqueous Humor Following Subconjunctival ENV905 Concentra-
Concentra- tion of tion of Study Formulation Study Param- DFBA DFB
Number (.mu.g DFBA) Day eter (ng/mL) (ng/mL) ENV905- ENV-1I- 9 Mean
BLQ 0.039 PRE-004 115-1 SD NA 0.088 (413) 21 Mean BLQ BLQ SD NA NA
28 Mean BLQ BLQ SD NA NA ENV905- ENV-1I- 9 Mean BLQ 0.138 PRE-004
115-1 SD NA 0.171 (1,239) 21 Mean BLQ 0.056 SD NA 0.112 28 Mean BLQ
0.0436 SD NA 0.0825 ENV905- ENV-1I- 9 Mean BLQ BLQ PRE-006 115-16-1
SD NA NA (390) 15 Mean BLQ 0.0368 SD NA 0.0735 24 Mean BLQ 0.0206
SD NA 0.0412
TABLE-US-00040 TABLE 39 Concentration of DFBA and DFB in Rabbit
Aqueous Humor Following Intracameral ENV905 Concentra- Concentra-
tion of tion of Study Formulation Study Param- DFBA DFB Number
(.mu.g DFBA) Day eter (ng/mL) (ng/mL) ENV905- ENV-1I- 9 Mean BLQ
BLQ PRE-004 115-1 SD NA NA (202) 21 Mean BLQ BLQ SD NA NA 28 Mean
BLQ BLQ SD NA NA ENV905- ENV-1I- 9 Mean BLQ BLQ PRE-006 115-8-7 SD
NA NA (40) 15 Mean BLQ 0.0278 SD NA 0.0555 24 Mean BLQ BLQ SD NA NA
ENV905- ENV-1I- 9 Mean BLQ BLQ PRE-006 115-8-5 SD NA NA (74) 15
Mean BLQ 0.0278 SD NA 0.0555 24 Mean BLQ 0.0143 SD NA 0.0287
[0420] Conjunctiva Concentration Data from Pharmacology Study
ENV905-PRE-004
[0421] Conjunctiva samples were taken at study termination in
ENV905-PRE-004 to gain an understanding of how much DFBA and DFB
remained at 28 days post-dose.
[0422] The formulations assessed in this study are not fully
representative of the clinical candidate formulations that are
planned for continued development, as they differ in excipient
content. There was no detectable DFBA or DFB in the placebo
samples. Detectable DFBA and DFB was present in 2 out of 8 samples
at 28 days following the 413 .mu.g difluprednate implant, and 4 out
of 8 samples at 28 days following 1,239 difluprednate implant.
Analysis of conjunctiva for concentration of DFBA and DFB following
dosing of the clinical candidate formulations of ENV905 has not
been conducted. See, Table 40.
TABLE-US-00041 TABLE 40 Concentration of DFBA and DFB in Rabbit
Superior Conjunctiva Following Subconjunctival ENV905 Concentra-
Concentra- tion of tion of Study Formulation Study Param- DFBA DFB
Number (.mu.g DFBA) Day eter (ng/g) (ng/g) ENV905- ENV-1I- 28 Mean
292.6 .sup. 27380.sup.1 PRE-004 115-1 SD 827.3 77426 (413) ENV905-
ENV-1I- 28 Mean 26900 .sup. 368878.5.sup.2 PRE-004 115-1 SD 56997
569916.1 (1,239) .sup.12 out of 8 samples were quantifiable, all
other samples were BLQ .sup.24 out of 8 samples were quantifiable,
all other samples were BLQ
[0423] Ocular and Systemic Concentration Data from Pharmacokinetic
Study ENV905-ADME-001
[0424] Plasma samples were collected from all surviving animals on
Days 1 (2 h), 2 (24 h), 4, 7, 14, 21, 28, 42, 56 and 84. Ocular
tissues from two animals per group per time point were collected on
Days 14, 28, 42, 56, and 84. Ocular matrixes collected included:
aqueous humor, cornea (enriched with trabecular meshwork),
iris/ciliary body, bulbar conjunctiva, subconjunctival dose site
(SCJ only), and retina.
[0425] The formulations assessed in this study are representative
of the clinical candidate formulations that are planned for
continued development.
[0426] Plasma exposure to Desacetyl Difluprednate (DFB) following
intracameral administration of ENV905-1 was noted at minimal
concentrations on Days 1 and 2, and was not quantifiable by Day 4.
See, FIG. 17 and Table 41.
[0427] Following SCJ delivery of ENV905-2, plasma exposure to
Desacetyl Difluprednate (DFB) was also minimal and was quantifiable
at very low levels through Day 14. See, FIG. 17 and Table 41.
TABLE-US-00042 TABLE 41 Concentration of DFB in Rabbit Plasma
Following Intracameral or Subconjunctival ENV905 No. of Concentra-
Formulation Im- tion of Study (.mu.g DFBA/ plants/ Study Param- DFB
Number Implant) Eye Day eter (ng/mL) ENV905- ENV905-1 3 1 (2 h)
Mean 2.583 ADME-001 (40.5) SD 0.779 IC Delivery 2 (24 h) Mean 0.062
SD 0.049 ENV905- ENV905-2 3 1 (2 h) Mean 3.850 ADME-001 (402.5) SD
2.703 SCJ Delivery 2 (24 h) Mean 3.475 SD 6.387 4 Mean 0.493 SD
0.09 7 Mean 0.134 SD 0.044 14 Mean 0.017 SD 0.028
[0428] Following IC delivery of ENV905-1, there was no quantifiable
exposure to Difluprednate (DFBA) except in 1 iris/ciliary body
sample on Day 28. All other samples were below the limit of
quantitation (BLQ). Exposure to Desacetyl Difluprednate (DFB) was
minimal on Day 14 in bulbar conjunctiva, TM-enriched cornea, and
iris/ciliary body, and was not quantifiable at Day 28. See, FIG.
18.
[0429] Following SCJ delivery of ENV905-2, Difluprednate (DFBA) was
quantifiable at the dose site and cornea through Day 56, and was
noted in the aqueous humor and retina at early time points.
Desacetyl Difluprednate (DFB) was observed at the dose site and
cornea through Day 84, in the bulbar conjunctiva through Day 56, in
the iris/ciliary body through Day 42, in the retina through Day 28,
and in the aqueous humor at early time points. See, FIG. 19.
Desacetyl Difluprednate (DFB) was also observed in the retina
through Day 28 and again in Day 84, but not at Days 42 and 56. See,
FIG. 19.
[0430] Ocular and Systemic Pharmacokinetics from Pharmacokinetic
Study ENV905-ADME-002
[0431] New Zealand White male rabbits per group per terminal time
point) were given a single bilateral administration of one, two, or
three ENV905 (difluprednate) Ophthalmic Implants (ENV905-1) via
intracameral delivery. For ENV905-1, the total dose delivered was
42.8, 85.6, or 128.4 .mu.g difluprednate per eye and 85.6, 171.2,
or 256.8 .mu.g difluprednate per animal, for the one, two, or three
implant groups, respectively. A separate group of animals were
administered topical DUREZOL.RTM. according to the clinical
standard of care paradigm for comparison purposes. DUREZOL.RTM.
dose administration was conducted as follows: one drop per eye four
times per day on Days 1-14, one drop per eye twice daily on Days
15-21, and one drop per eye once daily on Days 22-28, resulting in
a total dose of up to 1925 .mu.g difluprednate per eye and 3850
.mu.g difluprednate per animal over the course of the study.
[0432] Plasma and ocular matrixes (aqueous humor, bulbar
conjunctiva, cornea, trabecular meshwork, iris/ciliary body, and
retina) were collected on Days 1 (2 hours post dose), 2 (24 hours
post dose), 4, 7, 14, 21, 28, and 42, and analyzed for exposure to
Difluprednate (DFBA) and the active metabolite Diacetyl
Difluprednate (DFB). Samples for animals in the DUREZOL.RTM. group
were obtained on the same days, but were always collected at 30
minutes following the last dose administration of the day, so as to
capture the peak exposure following topical administration. Data
from these studies are provided in Table 42, and in FIGS. 21-24,
and 31-33. FIG. 21 shows the levels of DFB in the plasma (ng/mL),
FIGS. 22A and B compares the levels of Difluprednate to DFB in the
cornea (ng/mL), respectively; FIGS. 23A and B compares the levels
of Difluprednate to DFB in the trabecular meshwork (ng/mL),
respectively; FIGS. 24A and B compares the levels of Difluprednate
to DFB in the iris/ciliary body (ng/mL), respectively; FIGS. 31A
and B compares the levels of Difluprednate to DFB in the bulbar
conjunctiva (ng/mL), respectively; FIGS. 32A and B compares the
levels of Difluprednate to DFB in the retina (ng/mL), respectively;
and FIGS. 33A and B compares the levels of Difluprednate to DFB in
the aqueous humordif (ng/mL), respectively.
[0433] Topical DUREZOL.RTM. and a single bilateral administration
of one, two, or three ENV905-1 implants per eye were well tolerated
in the male NZW rabbit in this study for 42 days. Exposure to
parent DFBA and metabolite DFB following topical DUREZOL.RTM.
administration according to the clinical standard of care (1925
.mu.g/eye) was consistent in plasma (assessed for DFB only) and in
ocular matrixes across the dosing period when measured at 30
minutes post-dose, with the greatest exposure to DFB being in the
cornea and trabecular meshwork (AUC.sub.last 19996 and 15530
d*ng/g, respectively). Exposure to the active metabolite DFB
following administration of one ENV905-1 implant per eye (42.8
.mu.g/eye) was highest in iris/ciliary body (AUC.sub.last 13174
d*ng/g; See FIG. 24), to a lesser extent in cornea and trabecular
meshwork (AUC.sub.last 9329 and 8571 d*ng/g, respectively; See
FIGS. 22 and 23, respectively), with the least exposure in the
bulbar conjunctiva and retina (AUC.sub.last 135 and 92.1 d*ng/g,
respectively; See FIGS. 31 and 32), and this distribution paradigm
was generally mirrored in the two and three implants per eye groups
as well, with an increase in exposure observed as the dose
increased. ENV905-1 C.sub.max was on Day 1, and samples were
generally not quantifiable after the first 7-14 days of the study.
See FIG. 21. Generally, the shape of the exposure over time curve
was shifted left for ENV905 when compared with DUREZOL.RTM.
indicating increased exposure at earlier time points. See, e.g.,
FIG. 21. A direct comparison of AUC (d*ng/mL) for ENV905-1(low) and
DUREZOL.RTM. observed in plasma is shown in FIG. 26, in
iris/ciliary body is show in FIG. 27, and in trabecular meshwork is
shown in FIG. 28. These data demonstrate that following ENV905-1
administration, absorption and distribution within the ocular
matrixes is targeted to the anterior segment at physiologically
relevant concentrations, and the concentration of difluprednate is
greatest in the tissues most relevant to the therapeutic
indication. Additionally, the duration of difluprednate exposure in
ocular matrixes is generally limited to the most relevant time
points for inflammation suppression for this indication and is
particularly limited in the tissues linked to corticosteroid safety
concerns. Administration of ENV905 allows for significant
dose-sparing when compared with the standard of care regimen for
topical DUREZOL.RTM. due to the location of administration as well
as the release kinetics of ENV905.
TABLE-US-00043 TABLE 42 Pharmacokinetics from ENV905-ADME-002
Parent: Difluprednate (DFBA) Metabolite: Desacetyl Difluprednate
(DFB) C.sub.max C.sub.last AUC.sub.last C.sub.max C.sub.last
AUC.sub.last (ng/mL T.sub.max T.sub.1/2 (ng/mL T.sub.last (d*ng/mL
(ng/mL T.sub.max T.sub.1/2 (ng/mL T.sub.last (d*ng/mL Test Article
Matrix or g) (d) (d) or g) (d) or g) or g) (d) (d) or g) (d) or g)
DUREZOL .RTM. Plasma NA NA NA NA NA NA 0.41 2 NC 0.26 28 8.83 (up
to 1925 Aqueous 2.43 4 10.2 0.01 28 5.24 64 1 NC 49.2 28 1047
.mu.g/eye, 3850 Humor .mu.g/animal) Bulbar 6.52 28 NC 6.52 28 66.5
379 1 1.8 0.11 42 6528 Conjunctiva Cornea 56.8 7 NC 7.81 28 310 810
28 NC 0.43 42 19996 Trabecular 11.4 7 8.9 2.11 28 100 765 1 NC 717
28 15530 Meshwork Iris/Ciliary 0.65 7 NC 0.65 7 2.64 118 4 NC 109
28 2683 Body Retina 33.4 4 6.3 2.78 28 160 87.5 4 NC 25.8 28 749
ENV905-1 Plasma NA NA NA NA NA NA 0.99 1 NC 0.99 1 0.495 (42.8
.mu.g/eye, Aqueous 3595 1 NC 305 2 3131 3420 1 0.3 0.022 7 3323
85.6 Humor .mu.g/animal) Bulbar 0.575 1 NC 0.551 2 0.85 106 1 1.9
0.37 14 135 Conjunctiva Cornea 641 1 0.2 0.088 4 609 11283 1 3.2
0.65 14 9329 Trabecular 544 1 NC 88.3 2 523 9435 1 0.5 0.23 14 8571
Meshwork Iris/Ciliary 58125 1 NC 30020 2 71599 13115 1 0.4 0.2 7
13174 Body Retina 30.1 1 NC 0.77 2 23.1 89.9 1 0.8 0.33 7 92.1
ENV905-1 Plasma NA NA NA NA NA NA 1.98 1 NC 0.1 2 1.62 (85.6
.mu.g/eye, Aqueous 25065 1 NC 77 7 21679 9273 1 0.7 24 7 8621 171.2
Humor .mu.g/animal) Bulbar 18.8 4 NC 18.8 4 49.1 377 1 1.2 4.76 7
447 Conjunctiva Cornea 4029 1 0.5 0.665 7 3815 22750 1 0.5 0.21 14
19984 Trabecular 4215 1 0.5 1.04 7 4934 18050 1 0.7 28 7 18695
Meshwork Iris/Ciliary 181650 2 1.4 0.43 21 361171 32275 1 0.6 37.9
7 38503 Body Retina 363 4 NC 363 4 409 137 1 NC 45.5 4 169 ENV905-1
Plasma NA NA NA NA NA NA 2.75 1 0.5 0.04 4 2.44 (128.4 .mu.g/eye,
Aqueous 46050 1 0.7 0.023 14 41629 11158 1 0.6 5.57 7 10427 256.8
Humor .mu.g/animal) Bulbar 48.7 4 NC 0.098 21 175 233 1 0.9 1.63 7
716 Conjunctiva Cornea 5640 1 0.4 0.335 7 7777 39875 1 3.7 0.08 28
33262 Trabecular 16703 2 0.3 0.38 7 25656 24825 1 0.6 15.8 7 29174
Meshwork Iris/Ciliary 243775 1 1.3 1.13 28 460790 41700 1 0.7 0.09
28 49403 Body Retina 3011 4 NC 0.485 7 4508 222 4 0.8 0.83 7
764
[0434] Toxicology Summary for ENV905
[0435] Difluprednate, a corticosteroid prodrug of the active
metabolite DFB, is marketed as a 0.05% sterile preserved emulsion
for topical ocular delivery DUREZOL.RTM. is administered as a 4
times per day drop (approximately 100 .mu.g per day) in patients
recovering from ocular surgery or patients with endogenous anterior
uveitis. The toxicology profile of difluprednate was investigated
under NDA 22-212. Effects noted in nonclinical studies of
difluprednate included decreases in body weight and adrenal
effects, were deemed to be due to the pharmacologic action of the
molecule, and are well known glucocorticosteroid effects
(DUREZOL.RTM. Package Insert).
[0436] The disclosed ENV905 (difluprednate) Ophthalmic Implant is
an injectable difluprednate implant formulation using a
biocompatible polyethylene glycol (PEG)-based drug delivery system.
The implant is designed for ophthalmic administration via
subconjunctival (SCJ) or intracameral (IC) injection, with a single
dose administered following ocular surgery targeting duration of
action of 28 days. The PEG-based drug delivery system is comprised
of a blend of two PEGS that function as both diluent and binder,
and was designed for rapid dissolution of the implant and
concurrent release of difluprednate. The bioavailability and
sustained therapeutic effect of ENV905 over 28 days is governed by
multiple factors, including route of administration and the
physicochemical properties of the drug substance difluprednate.
ENV905 is formulated for the treatment of inflammation and pain
associated with ocular surgery. ENV905 is formulated as a solid,
rod-shaped implant of dimensions between 225-350 .mu.m in width by
2,925-6,000 .mu.m in length. The implants are loaded into the
needle of a single-use implant applicator and delivered into either
the subconjunctival space or the anterior chamber where they will
quickly disintegrate.
[0437] As shown in Table 43, multiple formulations of ENV905
administered by either SCJ or IC insertion were assessed for
tolerability in the pharmacology studies conducted in NZW rabbits
described above. Tolerability endpoints included body weights,
daily clinical observations, ophthalmic exams conducted by a
board-certified veterinary ophthalmologist, and ocular observations
during enucleation at sacrifice.
TABLE-US-00044 TABLE 43 ENV905 Formulations Tested in Tolerability
and Toxicology Studies in New Zealand White Rabbits Implant ENV905
Dimensions Number of Total Dose (.mu.g Route of Formulation ID PEG
Ratio (.mu.m) Implants/Eye difluprednate/Eye) Administration Study
Number ENV-1I-115-4 PEG 35K/PEG 100K (70/30) 300 .times. 300
.times. 6,000 2 0 SCJ ENV905-PRE-005 (Placebo) ENV-1I-53-28-1.sup.1
PEG 35K/PEG 100K (70/30) 300 .times. 300 .times. 6,000 2 432 SCJ
ENV905-PRE-005 ENV-1I-115-2 PEG 35K/PEG 100K (70/30) 300 .times.
300 .times. 6,000 2 826 SCJ ENV905-PRE-005 ENV905-1 PEG 100K/PEG
3,350 (89/11) 225 .times. 225 .times. 2,925 3 0 IC ENV905-PRE-008
Placebo ENV905-5 PEG 100K/PEG 3,350 (89/11) 130 .times. 180 .times.
1,500 3 0 IC ENV905-PRE-008 Placebo ENV905-5 PEG 100K/PEG 3,350
(89/11) 130 .times. 180 .times. 1,500 3 60 IC ENV905-PRE-008
ENV905-1 PEG 100K/PEG 3,350 (89/11) 225 .times. 225 .times. 2,925 3
0 IC ENV905-TOX-001 Placebo ENV905-1 PEG 100K/PEG 3,350 (89/11) 225
.times. 225 .times. 2,925 1, 2, or 3 44, 88, or 132 IC
ENV905-TOX-001
[0438] There were no observed adverse effects following a single
administration of ENV905 (range 40 to 1,239 .mu.g difluprednate per
eye) or placebo implant noted in any of the aforementioned
pharmacology studies.
[0439] A non-GLP tolerability study of SCJ ENV905 was conducted in
NZW rabbits. Male rabbits were administered a single bilateral SCJ
insertion of ENV905 or placebo implant and were followed for 28
days. Tolerability endpoints included body weights, daily clinical
observations, ophthalmic exams, and ocular histopathology at
sacrifice. Ophthalmic exams and histopathology assessment were
conducted by a board-certified veterinary ophthalmologist. ENV905
(0, 432, or 826 .mu.g difluprednate per eye) was well tolerated in
the NZW rabbit for 28 days, no adverse effects were noted, and no
evidence of ocular toxicity in clinical or histologic observation
was observed over 29 days. See, e.g., FIG. 16.
[0440] A non-GLP tolerability study of IC ENV905 was conducted in
NZW rabbits. New Zealand White rabbits (4 males/group) were
administered a single bilateral intracameral injection of three
ENV905 active or placebo implants, or received a single bilateral
intracameral injection without implants (sham), and were followed
for 7 days. The eyes were examined on Days 0 (baseline), 1 (8 hours
post-dose), and on Days 2 (.about.24 hours post-dose), 3 (.about.48
hours post-dose), 4, 5, 6, and 7 by a board-certified veterinary
ophthalmologist for signs of inflammation using the
Hackett-McDonald scoring system, and animals were observed daily.
Central and inferior corneal thickness was measured using an
ultrasonic pachymeter at baseline, approximately 8 hours
post-injection, and on Days 2, 3, 4, 5, 6, and 7. See FIGS. 25A and
25B, respectively. Non-contact specular microscopy (NCSM) images
were also taken on Days 0 (baseline), 1 (.about.8 hours post-dose),
and on Days 2, 3, 4, 5, 6, and 7. ENV905-1 and ENV905-5 implants
were well tolerated. However, the. ENV905-1 placebo implants were
associated with consistently increased central and inferior corneal
thickness and slightly higher histopathology scores compared to
ENV905-5 placebo and active implants or sham. See FIGS. 25A and
25B, respectively. These results indicates that the corneal
thickening effect observed with the ENV905-5 placebo is similar to
that observed with the sham (injection), and more corneal
thickening occurs with higher polymer matrix content (ENV905-1
placebo). Both ENV905-1 (active) and ENV905-5 (active) show a
reduction in corneal thickening. ENV905-5 placebo implants did not
induce any additional inflammation or corneal effects when compared
with sham, and the corneal thinning observed in the ENV905-5 active
group was associated with ocular corticosteroid administration as
expected and was not considered adverse. See FIGS. 25A and 25B,
respectively.
[0441] A GLP toxicology study of IC ENV905 was conducted in NZW
rabbits. Male and female rabbits received a single administration
of ENV905-1 and its relevant placebo, and were followed for 42
days. Assessment of toxicity was based on mortality, clinical
observations, qualitative food consumption, body weight, ophthalmic
examinations (slit lamp biomicroscopy and indirect ophthalmoscopy),
intraocular pressure (IOP) measurements, pachymetry,
electroretinography (ERG; scotopic tests), and clinical and
anatomic pathology. Blood samples were collected for toxicokinetic
evaluations. Male and female rabbits were each given three ENV905-1
Placebo ophthalmic implants; or one, two, or three ENV905-1
(difluprednate) ophthalmic implants, each containing 44.0 .mu.g
difluprednate/implant in the right and left eyes via intracameral
injection using ENV905-1 Applicators (dose levels of 44.0 (Low),
88.0 (Mid), or 132.0 (High) .mu.g/eye). No test article-related
clinical findings or effects on mortality, clinical observations,
qualitative food consumption, body weight, or body weight change
were noted. Ophthalmic findings and IOP changes in the active
ENV905-1 groups were limited to clinically beneficial effects on
the procedure-associated inflammation (See FIG. 29); signs of
inflammation noted in the placebo group were generally resolved by
Day 3. Changes in axial corneal thickness and in ERG were not
clinically important. Clinical pathology changes in all groups
given ENV905-1 implants included mildly increased glucose;
moderately decreased white blood cell and absolute lymphocyte,
eosinophil, and basophil counts; and mildly decreased calcium,
which resolved during the study period. Test article-related
microscopic findings and organ weight changes in systemic tissues
evaluated were limited to pharmacologic effects of the test article
in the liver and thymus at the interim sacrifice and are known
glucocorticoid effects; these were absent at the terminal
sacrifice. Test article-related microscopic observations in the
bulbar conjunctiva and eyes consisted of decreases in the severity
and incidence of mixed cell inflammation and heterophilic
infiltrates. No ENV905-1-related organ weight changes or
microscopic findings (systemic or ocular tissues) were present at
the terminal sacrifice, indicating findings had recovered by Day
43. No ENV905-1-related macroscopic observations were noted at the
interim or terminal sacrifice. Plasma concentration of Deacetyl
Difluprednate (DFB, active metabolite) peaked at 2 hours post-dose
(the first time point). See FIG. 30. ENV905-1 (High) had a
C.sub.max of 2.5 ng/mL. DFB concentrations were not quantifiable
following Day 4 for ENV905-1 (High). Due to the mild severity of
findings and the lack of impact on the health and wellbeing of
animals given 132.0 .mu.g/eye, effects at this dose were not
considered adverse. Thus, the no observed adverse effect level
(NOAEL) is 132.0 .mu.g/eye.
[0442] Thus, the tolerability profile of EN 905 and placebo implant
has been demonstrated in multiple non-GLP pharmacology studies, a
single non-GLP tolerability study, and a single GLP toxicology
study, and no findings have been observed to date that preclude the
continued development of ENV905.
[0443] Known Toxicology of Difluprednate (DUREZOL.RTM.)
[0444] The toxicology profile of difluprednate was investigated
under DUREZOL.RTM. NDA 22-212. In multiple studies performed in
rodents and non-rodents, subchronic and chronic toxicity tests of
difluprednate showed systemic effects such as suppression of body
weight gain; a decrease in lymphocyte count; atrophy of the
lymphatic glands and adrenal gland; and for local effects, thinning
of the skin; all of which were due to the pharmacologic action of
the molecule and are well known glucocorticosteroid effects. Most,
if not all of these effects were reversible after drug withdrawal.
The no-observed-effect-level (NOEL) for the subchronic and chronic
toxicity tests were consistent between species and ranged from
1-1.25 .mu.g/kg/day (DUREZOL.RTM. Package Insert).
[0445] Difluprednate was not genotoxic in vitro in the Ames test,
and in cultured mammalian cells CHL/IU (a fibroblastic cell line
derived from the lungs of newborn female Chinese hamsters). An in
vivo micronucleus test of difluprednate in mice was also negative.
Treatment of male and female rats with subcutaneous difluprednate
up to 10 .mu.g/kg/day prior to and during mating did not impair
fertility in either gender. Long-term studies have not been
conducted to evaluate the carcinogenic potential of difluprednate
(DUREZOL.RTM. Package Insert).
[0446] Difluprednate is categorized as Pregnancy Category C.
Difluprednate has been shown to be embryotoxic (decrease in
embryonic body weight and a delay in embryonic ossification) and
teratogenic (cleft palate and skeletal anomalies) when administered
subcutaneously to rabbits during organogenesis at a dose of 1-10
.mu.g/kg/day. The NOEL for these effects was 1 .mu.g/kg/day, and 10
.mu.g/kg/day was considered to be a teratogenic dose that was
concurrently found in the toxic dose range for fetuses and pregnant
females. Treatment of rats with 10 .mu.g/kg/day subcutaneously
during organogenesis did not result in any reproductive toxicity,
nor was it maternally toxic. At 100 .mu.g/kg/day after subcutaneous
administration in rats, there was a decrease in fetal weights and
delay in ossification, and effects on weight gain in the pregnant
females (DUREZOL.RTM. Package insert).
[0447] Known Toxicology of PEG Excipients
[0448] High molecular weight PEGs, also known as polyethylene oxide
(PEO) are polymers of ethylene oxide with a formula of
HO--(CH.sub.2--CH.sub.2--O).sub.n--H, where n is the number
(average) of ethylene glycol groups present in the molecule.
[0449] PEGs are not single chemical entities, but are mixtures of
various polymer chain lengths, and for some of the higher molecular
weight materials they can also be branched (Morpurgo 2004).
[0450] PEG is commonly used in cosmetics, PEGylated biologics, and
in numerous approved and marketed therapeutics (Inactive
Ingredients Database). These polymers are largely excreted
unchanged in the urine, with hepatobiliary clearance representing a
relatively minor pathway (Webster 2009). PEGS have been used
extensively in approved products across multiple routes of
administration including oral, topical, ophthalmic, rectal,
vaginal, intrasynovial, intra-articular, intramuscular, and
intravenous. PEGS are generally considered to have low toxicity and
have been tested across multiple routes of administration. PEGS
with a wide range of molecular weights have been shown to be safe
(Herold 1982, Smyth 1947, Smyth 1950, Smyth 1970, Webster 2009).
However, significant systemic exposure to PEGs via some routes of
administration (mainly topical application to burn victims) has
resulted in renal toxicity (Herold 1982). Studies of intravenous
PEG have shown that urinary clearance decreased with increasing PEG
molecular weight, similar to the tissue clearance, whereas liver
clearance increased with increasing PEG molecular weight (Yarnaoka
1993). After intravenous, intramuscular, and subcutaneous
administration, PEGs are generally excreted almost completely
within 24 hours, mainly in the urine (MAK collection). Furthermore,
intravenous administration of PEG 4,000,000 g/mol MW at dose levels
of up to 10 mg/kg had no evident toxicological effect (Smyth 1970).
PEGs are classified as Pregnancy Category C.
[0451] ENV905 ocular implant formulations may contain, in certain
embodiments, approximately 11.4 or 52.8 .mu.g of PEG 3,350 g/mol MW
and 92.6 or 427.2 .mu.g of PEG 100,000 g/mol MW per implant for the
intracameral or subconjunctival implants, respectively.
[0452] Based on current thinking for the proposed dose levels in
the GLP toxicology studies (up to 4 implants dosed bilaterally, if
feasible), animals could receive up to 422.4 .mu.g PEG 3,350 and
3,417.6 .mu.g PEG 100,000 per animal, while the exposure in the
placebo implant groups could be as much as twice that as the
placebo implants will be equal in mass to the ENV905 implants but
will not contain active pharmaceutical ingredient (API).
[0453] Systemic exposure to molecules administered via the IC or
SCJ routes is generally minimal, although exposure to PEG using
these routes is unknown. Clinical pathology parameters, including
renal factors BUN and creatinine, as well as liver enzyme levels,
will be measured predose and at sacrifice in all animals in the GLP
toxicology study to assess the effect of potential systemic
exposure to PEG; gross pathology at necropsy and organ weights will
also be monitored. Systemic histopathology is not planned.
[0454] ENV905 Implant Applicator
[0455] In embodiments, the ENV905 ocular implant administrations
have been performed using an ENV905 implant applicator; this
sterile applicator is comprised of either a 21 G to 22 G (for
ENV905-2), or a 25 G to 27 G (for ENV905-1, ENV905-3, ENV905-4, and
ENV.sup.-905-5) single-lumen hypodermic needle and stainless steel
pushrod attached to a standard 1-mL syringe.
[0456] ENV905 implants can be injected using the ENV905 ocular
implant applicator into the subconjunctival space or anterior
chamber of the eye using said injection tool.
[0457] The sterile implant applicator and the sterile ENV905
implants, in some aspects, can be packaged separately and loaded in
a sterile field in an operating room prior to administration to
patients scheduled for cataract surgery.
[0458] In some embodiments, ENV905 implants will be preloaded into
the sterile applicator, with the needle hub assembly of the implant
applicator functioning as a container closure for the implants.
[0459] ENV905 Implant Applicator Design
[0460] In embodiments, the applicator will be supplied as a
single-use, sterile, needle-based instrument for delivery of the
ENV905 implants into the subconjunctival space or anterior chamber.
In aspects, the applicator can utilize a 510K-approved, 21 G, 22 G,
23 G, 24 G, 25 G, 26 G, or 27 G, single-lumen hypodermic needle to
deliver the ENV905 implant(s). A stainless steel metal shaft
actuated via scroll wheel will advance the rod-shaped ENV905
implants from the lumen of the needle. The ENV905 implant
applicator, in some embodiments, will be terminally sterilized via
gamma irradiation following assembly and packaging. In some
aspects, the ENV905 implant applicator will be packaged in a
Tyvek.TM. pouch and terminally sterilized via gamma irradiation in
accordance with a validated sterilization method.
Prophetic Example 1
ENV905 in Cataract Surgery
[0461] The following example is prophetic in nature and describes
experiments to be performed and predicted results, rather than work
actually conducted or results actually achieved. Clinical efficacy
and safety is evaluated in randomized, active comparator controlled
study in which subjects after cataract extraction followed by
intraocular lens implantation are treated with DUREZOL
(difluprednate ophthalmic emulation 0.05%) or ENV905 containing
smaller dose of difluprednate vs. what is administered to the
patient via DUREZOL over the treatment period of 4 weeks after the
surgery. DUREZOL is administered as indicated 4 times daily
beginning 24 hours after surgery and continuing throughout the
first 2 weeks of the postoperative period, followed by 2 times
daily for a week and then a taper based on the response. The
presence of complete clearing (a cell count of 0) is assessed 8 and
15 days post-surgery. All adverse events are tracked and evaluated,
including adverse event of intraocular pressure (IOP) elevation.
The primary efficacy results based on presence of complete clearing
as described above show non-inferior control of ocular inflammation
in patients dosed with ENV905.
[0462] The adverse event of IOP elevation is often characterized as
IOP elevation by more than 10 mmHg. It has been shown for DUREZOL
that the adverse event of IOP elevation occurs approximately in the
range of 5-10% percent of the patients. ENV905, while demonstrating
non-inferior treatment effect, will demonstrate improved safety and
lesser incidence of adverse event of IOP elevation over DUREZOL's
incidence of 5-10%. Thus, it is expected that the incidence of
adverse events of IOP elevation is lower in patients dosed with
ENV905 compared to patients dosed with DUREZOL.
Prophetic Example 2
ENV905 in Endogenous Anterior Uveitis
[0463] The following example is prophetic in nature and describes
experiments to be performed and predicted results, rather than work
actually conducted or results actually achieved. Clinical efficacy
and safety is evaluated in randomized, active comparator controlled
study in which subjects who present with endogenous anterior
uveitis are assigned to DUREZOL (difluprednate ophthalmic emulation
0.05%) or ENV905 containing smaller dose of difluprednate vs. what
is administered to the patient via DUREZOL over the treatment
period. DUREZOL is administered as indicated 4 times daily
continuing throughout 2 weeks. The presence of complete clearing (a
cell count of 0) is assessed at 8 and at 15 days. All adverse
events are tracked and evaluated, including adverse event of
intraocular pressure (IOP) elevation. The primary efficacy results
based on presence of complete clearing as described above show
non-inferior control of ocular inflammation in patients dosed with
ENV905.
[0464] The adverse event ofIop elevation is often characterized as
IOP elevation by more than 10 mmHg. It has been shown for DUREZOL
that the adverse event of IOP elevation occurs approximately in the
range of 5-10% percent of the patients. ENV905, while demonstrating
non-inferior treatment effect, will demonstrate improved safety and
lesser incidence of adverse event of IOP elevation over DUREZOL's
incidence of 5-10%. Thus, it is expected that the incidence of
adverse events of IOP elevation is lower in patients dosed with
ENV905 compared to patients dosed with DUREZOL.
TABLE-US-00045 LIST OF ABBREVIATIONS Abbreviation Definition % RSD
relative standard deviation % v/v % volume/volume % w/w %
weight/weight .degree. C. degrees Celsius .degree. F. degrees
Fahrenheit .mu.g microgram .mu.L microliter .mu.m micrometer
.lamda..sub.avg average wavelength AH aqueous humor API active
pharmaceutical ingredient AUC.sub.last area under the plasma
concentration-time curve from time zero to the time of the last
quantifiable concentration BCVA best corrected visual acuity BID
twice daily BLQ below limit of quantitation BSC biological safety
cabinet c concentration CAS # chemical abstracts service number
CDER Center for Drug Evaluation and Research CFU colony-forming
unit cGMP current Good Manufacturing Practices C.sub.max maximal
concentration CMC chemistry, manufacturing, and controls cPs
centipoise Da daltons DFB 6.alpha.,9-difluoroprednisolone
17-butyrate (desacetyl difluprednate) DFBA
6.alpha.,9-difluoro-11.beta.,17,21-trihydroxypregna-1,4-diene-
3,20-dione 21 acetate 17-butyrate (difluprednate) DMF Drug Master
File DPT (diphenyl(2,4,6-trimethylbenzoyl) phosphine oxide/2-
hydroxy-2-methylpropiophenone) DTOP Division of Transplant and
Ophthalmology Products ETDRS Early Treatment Diabetic Retinopathy
Study EU endotoxin units FCR Fluorocur .RTM. (mold) FDA United
States Food and Drug Administration FID flame ionization detector
ft foot FTIR Fourier transform infrared spectrometry g gram G gauge
GC gas chromatography GLP Good Laboratory Practices GR
glucocorticoid receptor GCRBA glucocorticoid receptor-binding
activity H half HPLC high performance liquid chromatography HPLC RT
high performance liquid chromatography retention time IC
intracameral ICH International Conference on Harmonization IND
Investigational New Drug IOP intraocular pressure ISO International
Standard for Organization K thousand (number) kGy kilogray K.sub.i
inhibition constant L liter l.c. label claim LC-MS/MS liquid
chromatography and tandem mass spectrometry LLOC lower limit of
quantification M molar ME masked extension mg milligram min minute
mm millimeter MTD maximum tolerated dose MW average molecular
weight N, n, or No. number NA not applicable NDA New Drug
Application NF National Formulary ng nanogram NLT not less than nm
nanometer NMT not more than NOEL no-observed-effect-level NZW New
Zealand white (rabbit) PD pharmacodynamic PEG polyethylene glycol
PEO polyethylene oxide PET polyethylene terephthalate PK
pharmacokinetic ppm parts per million psi pounds per square inch
PTFE polytetrafluoroethylene q.s. ad quantities sufficient to make
QC quality control QID four times daily RH relative humidity RT
retention time SAE-04 mold resin component SCJ subconjunctival SD
standard deviation SDS sodium dodecyl sulfate sec seconds T or t
time TBD to be determined T.sub.max time of C.sub.max TMP
diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide US United States
USP United States Pharmacopoeia USP-NF United States Pharmacopoeia
- National Formulary UV ultraviolet VA visual acuity
TABLE-US-00046 SUMMARY OF EMBODIMENTS OF OCULAR IMPLANT
FORMULATIONS AI in AI in PEG % w/w in Total Dimension of Volume of
implant implant PEG (.mu.g) in implant implant implant Needle
implant implant (.mu.g) (% w/w) (3,350/100,000) (3,350/100,000)
(.mu.g) (ga) ENV905-1 225 .times. 225 .times. 2925 148,078,125
24-56 15-35 104-136 65-85 128-192 27 (11.4-15.0/92.6-121.0)
(7.2-9.4/57.9-75.7) ENV905-3 16-24 10-15 136-144 85-90 152-168
(15-15.8/121-128.2) (9.4-9.9/75.7-80.1) ENV905-4 8-12 .sup. 5-7.5
148-152 92.5-95.0 156-164 (16.3-16.7/131.7-135.3)
(10.2-10.5/82.3-84.6) ENV905-2 300 .times. 300 .times. 6000
540,000,000 320-480 40-60 320-480 40-60 640-960 21, 22
(35.2-52.8/284.8-427.2) (4.4-6.6/35.6-53.4) ENV905-5 130 .times.
180 .times. 1500 35,100,000 16-24 29.6-44.4 30-38 55.6-70.4 46-62
25, 26, 27 (3.3-4.2/26.7-33.8) (6.1-7.7/49.4-62.9)
INCORPORATION BY REFERENCE
[0465] All references, articles, publications, patents, patent
publications, and patent applications cited herein, are hereby
incorporated by reference in their entireties for all purposes.
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